Pyrazolopyrimidine pde9 inhibitors

ABSTRACT

which may be useful as therapeutic agents for the treatment of disorders associated with phosphodiesterase 9 (PDE9). The present invention also relates to the use of such compounds for treating cardiovascular and cerebrovascular diseases, such as hypertension, chronic kidney disease and heart failure, and neurological and psychiatric disorders, such as schizophrenia, psychosis or Huntington&#39;s disease, and those associated with striatal hypofunction or basal ganglia dysfunction.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. § 119(e) from U.S. Ser.No. 62/516,903, filed Jun. 8, 2017, and claims priority under 35 U.S.C.§ 119(e) from U.S. Ser. No. 62/665,840, filed May 2, 2018.

BACKGROUND OF THE INVENTION

The phosphodiesterases enzyme family hydrolyzes the cyclic nucleotidescyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate(cGMP). cGMP and cAMP are central to the control and regulation of amultitude of cellular events, both physiological and pathophysiological.One pathway for affecting the levels of cyclic nucleotides, such as cAMPand cGMP, is to alter or regulate the enzymes that degrade theseenzymes, known as 3′, 5′-cyclic nucleotide specific phosphodiesterases(PDEs). The PDE superfamily includes twenty one genes that encode foreleven families of PDEs. These families are further subdivided based oncatalytic domain homology and substrate specificity and include the: (1)cAM112 P specific, PDE4A-D, 7A and 7B, and 8A and 8B; (2) cGMP specific,PDE 5A, 6A-C, and 9A; and (3) those that are dual substrate, PDE 1A-C,2A, 3A and 3B, 10A, and 11A. The homology between the families, rangingfrom 20% to 45% suggests that it may be possible to develop selectiveinhibitors for each of these subtypes.

The identification of the phosphodiesterase PDE9 has been reported andwas distinguished from other PDEs on the basis of its amino acidsequence, functional properties, and tissue distribution. PDE9V isencoded by two genes (PDE9A and PDE9B) and is cGMP specific. At least 20different splice variants have been discovered (PDE9A1-PD9A20) in humanand in mouse. Structural study of PDE9A have been shown that its cDNA ofthe different splice variants share a high percentage of amino acididentity in the catalytic domain. However, despite its highestspecificity for cGMP among all the PDEs, PDE9A lacks a GAF domain, whosebinding of cGMP usually activates catalytic activity. Besides itsexpression in the kidney, spleen, and other peripheral organs, PDE9 iswidespread through the brain in mice, rats and humans, and has beenfound to be present in a variety of human tissues, including the testes,small intestine, skeletal muscle, smooth muscle in the vasculature,heart, lung, and thymus.

Inhibition of PDE9 is believed to be useful in the treatment ofcardiovascular and cerebrovascular diseases, such as hypertension andheart failure, and cognitive deficit associated with neurodegenerativeand psychiatric disorders and a variety of conditions or disorders thatwould benefit from increasing levels of cGMP within neurons, includingAlzheimer's disease, schizophrenia, and depression.

SUMMARY OF THE INVENTION

The present invention is directed to pyrazolopyrimidine compounds whichmay be useful as therapeutic agents for the treatment of disordersassociated with phosphodiesterase 9 (PDE9). The present invention alsorelates to the use of such compounds for treating cardiovascular andcerebrovascular diseases, such as hypertension and heart failure, andneurological and psychiatric disorders, such as schizophrenia, psychosisor Huntington's disease, and those associated with striatal hypofunctionor basal ganglia dysfunction.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of the formula I:

wherein:

-   A is a cyclobutyl ring, which is unsubsubstituted or substituted    with substituents selected from: fluoro and methyl;-   R¹, R² and R³ are independently selected from:    -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) C₁₋₆alkyl, which is unsubstituted or substituted with        substituents selected from: hydroxy and fluoro,    -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        substituents selected from fluoro,    -   (6) C₃₋₆cycloalkyl,    -   (7) C₂₋₆alkynyl, and    -   (8) —CN;-   R⁴ is selected from:    -   (1) hydrogen,    -   (2) —CH₃;    -   (3) —CF₃,    -   (4) —CH₂OH,    -   (5) —CO₂H, and    -   (6) —CH₂CH₃;-   R⁵ is a phenyl, pyridyl, pyrazinyl, pyrazolyl, pyrimidinyl,    pyridazinyl, thiazolyl, cyclohexyl or tetrahydropyranyl ring,    wherein the phenyl, pyridyl, pyrazinyl, pyrazolyl, pyrimidinyl,    pyridazinyl, thiazolyl, cyclohexyl or tetrahydropyranyl ring is    substituted with R^(1a), R^(1b) and R^(1c), wherein R^(1a), R^(1b)    and R^(1c) are independently selected from:    -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) C₁₋₆ alkyl, which is unsubstituted or substituted with        substituents selected from: hydroxy and fluoro,    -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        substituents selected from fluoro,    -   (6) C₃₋₆cycloalkyl, and    -   (7) —CN;-   or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIa:

wherein A, R² and R⁵ are defined herein; or a pharmaceuticallyacceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIaa:

wherein A, R² and R⁵ are defined herein; or a pharmaceuticallyacceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIaa′:

wherein A, R² and R⁵ are defined herein; or a pharmaceuticallyacceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIaa″:

wherein A, R² and R⁵ are defined herein; or a pharmaceuticallyacceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIab:

wherein A, R² and R⁵ are defined herein; or a pharmaceuticallyacceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIab′:

wherein A, R² and R⁵ are defined herein; or a pharmaceuticallyacceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIab′:

wherein A, R² and R⁵ are defined herein; or a pharmaceuticallyacceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIb:

wherein R², R⁵, R⁶ and R⁷ are defined herein; or a pharmaceuticallyacceptable salt thereof.

An embodiment of the present invention includes compounds wherein A is acyclobutyl ring, which is unsubstituted or substituted with R⁶ and R⁷,wherein R⁶ and R⁷ are selected from:

-   -   (1) hydrogen,    -   (2) fluoro, and    -   (3) —CH₃.

An embodiment of the present invention includes compounds wherein A is acyclobutyl ring, which is unsubstituted or substituted with one or morefluoro.

An embodiment of the present invention includes compounds wherein R¹, R²and R³ are independently selected from:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) C₁₋₆alkyl, which is unsubstituted or substituted with        substituents selected from: hydroxy and fluoro,    -   (5) —O—C₁₋₆ alkyl, which is unsubstituted or substituted with        substituents selected from fluoro,    -   (6) C₃₋₆ cycloalkyl,    -   (7) C₂₋₄alkynyl, and    -   (8) —CN.

An embodiment of the present invention includes compounds wherein R¹, R²and R³ are independently selected from:

-   -   (1) hydrogen,    -   (2) fluoro,    -   (3) chloro,    -   (4) hydroxyl,    -   (5) C₁₋₂alkyl, which is unsubstituted or substituted with one or        more fluoro,    -   (6) —O—C₁₋₂alkyl, which is unsubstituted or substituted with one        or more fluoro,    -   (7) C₃₋₅cycloalkyl, and    -   (8) C₂₋₃alkynyl.

An embodiment of the present invention includes compounds wherein R¹ ishydrogen and R³ is hydrogen.

An embodiment of the present invention includes compounds wherein R¹ ishydrogen, R³ is hydrogen and R² is selected from:

-   -   (1) hydrogen,    -   (2) fluoro,    -   (3) chloro,    -   (4) hydroxyl,    -   (5) C₁₋₂ alkyl, which is unsubstituted or substituted with one        or more fluoro,    -   (6) —O—C₁₋₂alkyl, which is unsubstituted or substituted with one        or more fluoro, and    -   (7) C₃₋₅cycloalkyl, and    -   (8) C₂₋₃alkynyl.

An embodiment of the present invention includes compounds wherein R¹ ishydrogen, R³ is hydrogen and R² is selected from:

-   -   (1) hydrogen,    -   (2) fluoro,    -   (3) chloro,    -   (4) bromo,    -   (5) hydroxyl,    -   (6) —CH₃,    -   (7) —OCH₃,    -   (8) —CHF₂,    -   (9) —CF₃,    -   (10) —OCHF₂,    -   (11) —OCF₃,    -   (12) —CH₂CH₃,    -   (13) —CH(CH₃)₂,    -   (14) —C(CH₃)₃,    -   (15) —C═CH, and    -   (16) cyclopropyl.

An embodiment of the present invention includes compounds wherein R⁴ ishydrogen. An embodiment of the present invention includes compoundswherein R⁴ is —CH₃.

An embodiment of the present invention includes compounds wherein R⁵ isa phenyl, pyridyl, pyrazinyl, pyrazolyl, pyrimidinyl, pyridazinyl orthiazolyl ring, wherein the phenyl, pyridyl, pyrazinyl, pyrazolyl,pyrimidinyl, pyridazinyl or thiazolyl ring is substituted with R^(1a),R^(1b) and R^(1c), wherein R^(1a), R^(1b) and R^(1c) are independentlyselected from:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) C₁₋₆ alkyl, which is unsubstituted or substituted with        substituents selected from: hydroxy and fluoro,    -   (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        substituents selected from fluoro,    -   (6) C₃₋₆cycloalkyl, and    -   (7) —CN.

An embodiment of the present invention includes compounds wherein R⁵ isa phenyl, pyridyl, pyrazinyl, pyrazolyl, pyrimidinyl, pyridazinyl orthiazolyl ring, wherein the phenyl, pyridyl, pyrazinyl, pyrazolyl,pyrimidinyl, pyridazinyl or thiazolyl ring is substituted with R^(1a),R^(1b) and R^(1c), wherein R^(1a), R^(1b) and R^(1c) are independentlyselected from:

-   -   (1) hydrogen,    -   (2) fluoro,    -   (3) C₁₋₂alkyl, which is unsubstituted or substituted with one or        more fluoro,    -   (4) —O—C₁₋₂alkyl, which is unsubstituted or substituted with one        or more fluoro,    -   (5) cyclopropyl, and    -   (6) —CN.

An embodiment of the present invention includes compounds wherein R⁵ isa phenyl, pyridyl, pyrazinyl, pyrazolyl, pyrimidinyl, pyridazinyl orthiazolyl ring, wherein the phenyl, pyridyl, pyrazinyl, pyrazolyl,pyrimidinyl, pyridazinyl or thiazolyl ring is substituted with R^(1a),R^(1b) and R^(1c), wherein R^(1a), R^(1b) and R^(1c) are independentlyselected from:

-   -   (1) hydrogen,    -   (2) fluoro,    -   (3) —CH₃,    -   (4) —CHF,    -   (5) —CF₃,    -   (6) —OCHF₂,    -   (7) —OCF₃,    -   (8) —OCHF₂,    -   (9) —OCF₃,    -   (10) cyclopropyl, and    -   (11) —CN.

An embodiment of the present invention includes compounds wherein R⁵ isa phenyl ring. An embodiment of the present invention includes compoundswherein R⁵ is a pyridyl ring. An embodiment of the present inventionincludes compounds wherein R⁵ is a pyrazinyl ring.

An embodiment of the present invention includes compounds wherein R⁵ isa pyrazolyl ring.An embodiment of the present invention includes compounds wherein R⁵ isa pyrimidinyl ring.An embodiment of the present invention includes compounds wherein R⁵ isa pyridazinyl ring.An embodiment of the present invention includes compounds wherein R⁵ isa thiazolyl ring.An embodiment of the present invention includes compounds wherein R⁵ isa cyclohexyl ring.An embodiment of the present invention includes compounds wherein R⁵ isa tetrahydropyranyl ring.

An embodiment of the present invention includes compounds R^(1b) ishydrogen and R^(1c) is hydrogen, and R^(1a) is selected from:

-   -   (1) hydrogen,    -   (2) fluoro,    -   (3) —CH₃,    -   (4) —CHF₂,    -   (5) —CF₃,    -   (6) —OCHF₂,    -   (7) —OCF₃,    -   (8) cyclopropyl, and    -   (9) —CN.

An embodiment of the present invention includes compounds wherein R⁵ isselected from:

-   -   (1) 4-fluorophenyl,    -   (2) 4-cyanophenyl,    -   (3) 3-(trifluoromethyl)phenyl,    -   (4) 4-(trifluoromethyl)phenyl,    -   (5) 3,4-difluorophenyl, and    -   (6) 6-(trifluoromethyl)pyridin-3-yl.

An embodiment of the present invention includes a compound which isselected from:

-   1-(1-(4-fluorophenyl)ethyl)-4-oxo-6-(2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((S)-1-(4-fluorophenyl)ethyl)-4-oxo-6-((1R,2R)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((S)-1-(4-fluorophenyl)ethyl)-4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((R)-1-(4-fluorophenyl)ethyl)-4-oxo-6-((1R,2R)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((R)-1-(4-fluorophenyl)ethyl)-4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   4-oxo-6-(2-(pyrimidin-2-yl)cyclobutyl)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   4-oxo-6-((1R,2R)-2-(pyrimidin-2-yl)cyclobutyl)-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   4-oxo-6-((1R,2R)-2-(pyrimidin-2-yl)cyclobutyl)-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   4-oxo-6-(2-(pyrimidin-2-yl)cyclobutyl)-1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   4-oxo-6-((1R,2R)-2-(pyrimidin-2-yl)cyclobutyl)-1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-[1-(4-cyanophenyl)ethyl]-4-oxo-6-(2-pyrimidin-2-ylcyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((S)-1-(4-cyanophenyl)ethyl)-4-oxo-6-((1R,2R)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((S)-1-(4-cyanophenyl)ethyl)-4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((R)-1-(4-cyanophenyl)ethyl)-4-oxo-6-((1R,2R)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((R)-1-(4-cyanophenyl)ethyl)-4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-(1-(3,4-difluorophenyl)ethyl)-4-oxo-6-(2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((S)-1-(3,4-difluorophenyl)ethyl)-4-oxo-6-((1R,2R)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((S)-1-(3,4-difluorophenyl)ethyl)-4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((R)-1-(3,4-difluorophenyl)ethyl)-4-oxo-6-((1R,2R)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((R)-1-(3,4-difluorophenyl)ethyl)-4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   4-oxo-6-[2-pyrimidin-2-ylcyclobutyl]-1-{1-[4-(trifluoromethyl)phenyl]ethyl}-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   4-oxo-6-((1R,2R)-2-(pyrimidin-2-yl)cyclobutyl)-1-((S)-1-(4-(trifluoromethyl)phenyl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-1-((S)-1-(4-(trifluoromethyl)phenyl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   4-oxo-6-((1R,2R)-2-(pyrimidin-2-yl)cyclobutyl)-1-((R)-1-(4-(trifluoromethyl)phenyl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-1-((R)-1-(4-(trifluoromethyl)phenyl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   4-oxo-6-[2-pyrimidin-2-ylcyclobutyl]-1-{1-[3-(trifluoromethyl)phenyl]ethyl}-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   4-oxo-6-((1R,2R)-2-(pyrimidin-2-yl)cyclobutyl)-1-((S)-1-(3-(trifluoromethyl)phenyl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-1-((S)-1-(3-(trifluoromethyl)phenyl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   4-oxo-6-((1R,2R)-2-(pyrimidin-2-yl)cyclobutyl)-1-((R)-1-(3-(trifluoromethyl)phenyl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-1-((R)-1-(3-(trifluoromethyl)phenyl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   4-oxo-6-(2-(pyrimidin-2-yl)cyclobutyl)-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   4-oxo-6-((1R,2R)-2-(pyrimidin-2-yl)cyclobutyl)-1-((S)-1-(5-(trifluoromethyl)pyrazin-2-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-1-((S)-1-(5-(trifluoromethyl)pyrazin-2-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   4-oxo-6-((1R,2R)-2-(pyrimidin-2-yl)cyclobutyl)-1-((R)-1-(5-(trifluoromethyl)pyrazin-2-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-1-((R)-1-(5-(trifluoromethyl)pyrazin-2-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-(2-(5-methylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1R,2R)-2-(5-methylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1S,2S)-2-(5-methylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1R,2R)-2-(5-methylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1S,2S)-2-(5-methylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   4-oxo-6-(2-(pyrimidin-2-yl)cyclobutyl)-1-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   4-oxo-6-((1R,2R)-2-(pyrimidin-2-yl)cyclobutyl)-1-((S)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-1-((S)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   4-oxo-6-((1R,2R)-2-(pyrimidin-2-yl)cyclobutyl)-1-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-1-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-(1-(6-(difluoromethyl)pyridin-3-yl)ethyl)-4-oxo-6-(2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((S)-1-(6-(difluoromethyl)pyridin-3-yl)ethyl)-4-oxo-6-((1R,2R)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((S)-1-(6-(difluoromethyl)pyridin-3-yl)ethyl)-4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((R)-1-(6-(difluoromethyl)pyridin-3-yl)ethyl)-4-oxo-6-((1R,2R)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((R)-1-(6-(difluoromethyl)pyridin-3-yl)ethyl)-4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((S)-1-(6-(difluoromethyl)pyridin-3-yl)ethyl)-4-oxo-6-((1R,2S)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((S)-1-(6-(difluoromethyl)pyridin-3-yl)ethyl)-4-oxo-6-((1S,2R)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((R)-1-(6-(difluoromethyl)pyridin-3-yl)ethyl)-4-oxo-6-((1R,2S)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((R)-1-(6-(difluoromethyl)pyridin-3-yl)ethyl)-4-oxo-6-((1S,2R)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   4-oxo-6-(2-(pyrimidin-2-yl)cyclobutyl)-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   4-oxo-6-((1R,2R)-2-(pyrimidin-2-yl)cyclobutyl)-1-((S)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-1-((S)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   4-oxo-6-((1R,2R)-2-(pyrimidin-2-yl)cyclobutyl)-1-((R)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-1-((R)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-(1-(6-cyclopropylpyridin-3-yl)ethyl)-4-oxo-6-(2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((S)-1-(6-cyclopropylpyridin-3-yl)ethyl)-4-oxo-6-((1R,2R)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((S)-1-(6-cyclopropylpyridin-3-yl)ethyl)-4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((R)-1-(6-cyclopropylpyridin-3-yl)ethyl)-4-oxo-6-((1R,2R)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((R)-1-(6-cyclopropylpyridin-3-yl)ethyl)-4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((S)-1-(6-cyclopropylpyridin-3-yl)ethyl)-4-oxo-6-((1R,2S)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((S)-1-(6-cyclopropylpyridin-3-yl)ethyl)-4-oxo-6-((1S,2R)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;    1-((R)-1-(6-cyclopropylpyridin-3-yl)ethyl)-4-oxo-6-((1R,2S)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((R)-1-(6-cyclopropylpyridin-3-yl)ethyl)-4-oxo-6-((1S,2R)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-(2-(5-bromopyrimidin-2-yl)cyclobutyl)-4-oxo-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1R,2R)-2-(5-bromopyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1S,2S)-2-(5-bromopyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1R,2R)-2-(5-bromopyrimidin-2-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1S,2S)-2-(5-bromopyrimidin-2-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-(2-(5-(difluoromethoxy)pyrimidin-2-yl)cyclobutyl)-4-oxo-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1R,2R)-2-(5-(difluoromethoxy)pyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1S,2S)-2-(5-(difluoromethoxy)pyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1R,2R)-2-(5-(difluoromethoxy)pyrimidin-2-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1S,2S)-2-(5-(difluoromethoxy)pyrimidin-2-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-(2-(5-ethylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1R,2R)-2-(5-ethylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1S,2S)-2-(5-ethylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1R,2R)-2-(5-ethylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1S,2S)-2-(5-ethylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-(1-(5-fluoropyridin-3-yl)ethyl)-4-oxo-6-(2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((S)-1-(5-fluoropyridin-3-yl)ethyl)-4-oxo-6-((1R,2R)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((S)-1-(5-fluoropyridin-3-yl)ethyl)-4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((R)-1-(5-fluoropyridin-3-yl)ethyl)-4-oxo-6-((1R,2R)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((R)-1-(5-fluoropyridin-3-yl)ethyl)-4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-(1-(1-methyl-1H-pyrazol-4-yl)ethyl)-4-oxo-6-(2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((S)-1-(1-methyl-1H-pyrazol-4-yl)ethyl)-4-oxo-6-((1R,2R)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((S)-1-(1-methyl-1H-pyrazol-4-yl)ethyl)-4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((R)-1-(1-methyl-1H-pyrazol-4-yl)ethyl)-4-oxo-6-((1R,2R)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((R)-1-(1-methyl-1H-pyrazol-4-yl)ethyl)-4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-(1-(6-cyclopropylpyridin-3-yl)ethyl)-6-(2-(5-fluoropyrimidin-2-yl)cyclobutyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((S)-1-(6-cyclopropylpyridin-3-yl)ethyl)-6-((1R,2R)-2-(5-fluoropyrimidin-2-yl)cyclobutyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((S)-1-(6-cyclopropylpyridin-3-yl)ethyl)-6-((1S,2S)-2-(5-fluoropyrimidin-2-yl)cyclobutyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((R)-1-(6-cyclopropylpyridin-3-yl)ethyl)-6-((1R,2R)-2-(5-fluoropyrimidin-2-yl)cyclobutyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((R)-1-(6-cyclopropylpyridin-3-yl)ethyl)-6-((1S,2S)-2-(5-fluoropyrimidin-2-yl)cyclobutyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   4-oxo-6-(2-(pyrimidin-2-yl)cyclobutyl)-1-(1-(2-(trifluoromethyl)thiazol-5-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   4-oxo-6-((1R,2R)-2-(pyrimidin-2-yl)cyclobutyl)-1-((S)-1-(2-(trifluoromethyl)thiazol-5-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-1-((S)-1-(2-(trifluoromethyl)thiazol-5-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   4-oxo-6-((1R,2R)-2-(pyrimidin-2-yl)cyclobutyl)-1-((R)-1-(2-(trifluoromethyl)thiazol-5-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-1-((R)-1-(2-(trifluoromethyl)thiazol-5-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-(1-(2-cyclopropylpyrimidin-5-yl)ethyl)-6-(2-(5-fluoropyrimidin-2-yl)cyclobutyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((S)-1-(2-cyclopropylpyrimidin-5-yl)ethyl)-6-((1R,2R)-2-(5-fluoropyrimidin-2-yl)cyclobutyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((S)-1-(2-cyclopropylpyrimidin-5-yl)ethyl)-6-((1S,2S)-2-(5-fluoropyrimidin-2-yl)cyclobutyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((R)-1-(2-cyclopropylpyrimidin-5-yl)ethyl)-6-((1R,2R)-2-(5-fluoropyrimidin-2-yl)cyclobutyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((R)-1-(2-cyclopropylpyrimidin-5-yl)ethyl)-6-((1S,2S)-2-(5-fluoropyrimidin-2-yl)cyclobutyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-(2-(5-ethynylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1R,2R)-2-(5-ethynylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1S,2S)-2-(5-ethynylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1R,2R)-2-(5-ethynylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1S,2S)-2-(5-ethynylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-(2-(5-fluoropyrimidin-2-yl)cyclobutyl)-4-oxo-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1R,2R)-2-(5-fluoropyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1S,2S)-2-(5-fluoropyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1R,2R)-2-(5-fluoropyrimidin-2-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1S,2S)-2-(5-fluoropyrimidin-2-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-(2-(5-fluoropyrimidin-2-yl)cyclobutyl)-4-oxo-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1R,2R)-2-(5-fluoropyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1S,2S)-2-(5-fluoropyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1R,2R)-2-(5-fluoropyrimidin-2-yl)cyclobutyl)-4-oxo-1-((R)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1S,2S)-2-(5-fluoropyrimidin-2-yl)cyclobutyl)-4-oxo-1-((R)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-(1-methyl-2-(pyrimidin-2-yl)cyclobutyl)-4-oxo-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1R,2R)-1-methyl-2-(pyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1S,2S)-1-methyl-2-(pyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1R,2R)-1-methyl-2-(pyrimidin-2-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1S,2S)-1-methyl-2-(pyrimidin-2-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-(2-(5-cyanopyrimidin-2-yl)cyclobutyl)-4-oxo-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1R,2R)-2-(5-cyanopyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1S,2S)-2-(5-cyanopyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1R,2R)-2-(5-cyanopyrimidin-2-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1S,2S)-2-(5-cyanopyrimidin-2-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-(2-(5-cyclopropylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1R,2R)-2-(5-cyclopropylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1S,2S)-2-(5-cyclopropylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1R,2R)-2-(5-cyclopropylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1S,2S)-2-(5-cyclopropylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-(1-(2-cyclopropylpyrimidin-5-yl)ethyl)-4-oxo-6-(2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((S)-1-(2-cyclopropylpyrimidin-5-yl)ethyl)-4-oxo-6-((1R,2R)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((S)-1-(2-cyclopropylpyrimidin-5-yl)ethyl)-4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((R)-1-(2-cyclopropylpyrimidin-5-yl)ethyl)-4-oxo-6-((1R,2R)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((R)-1-(2-cyclopropylpyrimidin-5-yl)ethyl)-4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-(2-(5-methoxypyrimidin-2-yl)cyclobutyl)-4-oxo-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1R,2R)-2-(5-methoxypyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1S,2S)-2-(5-methoxypyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1R,2R)-2-(5-methoxypyrimidin-2-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1S,2S)-2-(5-methoxypyrimidin-2-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-(1-(5-fluoropyridin-2-yl)ethyl)-4-oxo-6-(2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((S)-1-(5-fluoropyridin-2-yl)ethyl)-4-oxo-6-((1R,2R)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((S)-1-(5-fluoropyridin-2-yl)ethyl)-4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((S)-1-(5-fluoropyridin-2-yl)ethyl)-4-oxo-6-((1R,2S)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   1-((S)-1-(5-fluoropyridin-2-yl)ethyl)-4-oxo-6-((1S,2R)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-(2-(5-(difluoromethyl)pyrimidin-2-yl)cyclobutyl)-4-oxo-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1R,2R)-2-(5-(difluoromethyl)pyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1S,2S)-2-(5-(difluoromethyl)pyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1R,2S)-2-(5-(difluoromethyl)pyrimidin-2-yl)cyclobutyl)-4-oxo-1-4S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1S,2R)-2-(5-(difluoromethyl)pyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-(2-(5-chloropyrimidin-2-yl)cyclobutyl)-4-oxo-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1R,2R)-2-(5-chloropyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1S,2S)-2-(5-chloropyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1R,2R)-2-(5-chloropyrimidin-2-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1S,2S)-2-(5-chloropyrimidin-2-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1S,2S)-2-(4,6-dimethylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1S,2S)-2-(4-(difluoromethyl)pyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)-pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1S,2S)-2-(4,6-di-tert-butylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)-pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1S,2S)-2-(4-cyclopropylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)-pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1R,2R)-2-(4-(difluoromethyl)pyrimidin-2-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)-pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1R,2R)-2-(4,6-bis(difluoromethyl)pyrimidin-2-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1R,2R)-2-(4-methylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1R,2R)-2-(4,6-di-tert-butylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)-pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1R,2R)-2-(4-methylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1R,2R)-2-(4,6-dimethylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-(2-(4-(tert-butyl)pyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1R,2R)-2-(4,6-di-tert-butylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)-pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;-   6-((1R,2R)-2-(4-(difluoromethyl)pyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)-pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;    and-   6-((1R,2R)-2-(4-cyclopropylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)-pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;    or a pharmaceutically acceptable salt thereof.

Certain embodiments of the present invention include a compound which isselected from the subject compounds of the Examples herein or apharmaceutically acceptable salt thereof.

The compounds of the present invention may contain one or moreasymmetric centers and can thus occur as racemates and racemic mixtures,single enantiomers, diastereomeric mixtures and individualdiastereomers. Additional asymmetric centers may be present dependingupon the nature of the various substituents on the molecule. Each suchasymmetric center will independently produce two optical isomers and itis intended that all of the possible optical isomers and diastereomersin mixtures and as pure or partially purified compounds are includedwithin the ambit of this invention. The present invention is meant tocomprehend all such isomeric forms of these compounds. Likewise, thepresent invention includes tautomeric forms of the compounds disclosedherein. Formula I shows the structure of the class of compounds withoutspecific stereochemistry. At least some of the chemical names ofcompounds of the invention as set forth in this application may havebeen generated on an automated basis by use of commercially availablechemical naming software programs, and have not been independentlyverified.

The independent syntheses of these diastereomers or theirchromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the x-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration. If desired, racemic mixtures ofthe compounds may be separated so that the individual enantiomers areisolated. The separation can be carried out by methods well known in theart, such as the coupling of a racemic mixture of compounds to anenantiomerically pure compound to form a diastereomeric mixture,followed by separation of the individual diastereomers by standardmethods, such as fractional crystallization or chromatography. Thecoupling reaction is often the formation of salts using anenantiomerically pure acid or base. The diasteromeric derivatives maythen be converted to the pure enantiomers by cleavage of the addedchiral residue. The racemic mixture of the compounds can also beseparated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

The compounds of the present invention may exist in different tautomericforms, and all such forms are embraced within the scope of theinvention. Also, for example, all keto-enol, lactam-lactim andamide-imidic acid forms of the compounds are included in the invention.Thus, for example, the compounds of the invention of the formula:

and their tautomers:

are both contemplated as being within the scope of the compounds of theinvention, and the depiction of a particular tautomeric form embracesall other tautomeric forms.

As appreciated by those of skill in the art, halogen or halo as usedherein are intended to include fluoro, chloro, bromo and iodo. The termC₁₋₆, as in C₁₋₆alkyl is defined to identify the group as having 1, 2,3, 4, 5 or 6 carbons in a linear or branched arrangement, such thatC₁₋₆alkyl specifically includes methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, tert-butyl, pentyl, and hexyl. Substituents (such asR¹, R², R³, R^(1a), R^(1b), R^(1c), R⁶ and R⁷) may be absent if thevalency of the group to which they are attached does not permit suchsubstitution. A group which is designated as being independentlysubstituted with substituents may be independently substituted withmultiple numbers of such substituents.

The present invention also includes all pharmaceutically acceptableisotopic variations of a compound of the Formula I in which one or moreatoms is replaced by atoms having the same atomic number, but an atomicmass or mass number different from the atomic mass or mass numberusually found in nature. Such compounds are identical to those disclosedherein, but for the fact that one or more atoms are replaced by an atomhaving an atomic mass or mass number different from the atomic mass ormass number usually found in nature. Examples of isotopes that can beincorporated into the compounds of the invention include isotopes ofhydrogen such as ²H and ³H, carbon such as ¹¹C, ¹³C and ¹⁴C, nitrogensuch as ¹³N and ¹⁵N, oxygen such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus such as³²P, sulfur such as ³⁵S, fluorine such as ¹⁸F, iodine such as ¹²³I and¹²⁵I, and chlorine such as ³⁶Cl. Certain isotopically-labelled compoundsof Formula I, for example those incorporating a radioactive isotope, areuseful in drug and/or substrate tissue distribution studies. Theradioactive isotopes tritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, areparticularly useful for this purpose in view of their ease ofincorporation and ready means of detection. Substitution with heavierisotopes such as deuterium, i.e. ²H, may afford certain therapeuticadvantages resulting from greater metabolic stability, for example,increased in vivo half-life or reduced dosage requirements, and hencemay be preferred in some circumstances. Substitution with positronemitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, can be useful inPositron Emission Topography (PET) studies for examining substratereceptor occupancy. An embodiment of the present invention includescompounds that are substituted with a positron emitting isotope. Anembodiment of the present invention includes compounds that aresubstituted with a ¹¹C isotope. An embodiment of the present inventionincludes compounds that are substituted with an ¹⁸F isotope. In thecompounds of the invention, the atoms may exhibit their natural isotopicabundances, or one or more of the atoms may be artificially enriched ina particular isotope having the same atomic number, but an atomic massor mass number different from the atomic mass or mass numberpredominantly found in nature. The present invention is meant to includeall suitable isotopic variations of the compounds of the invention. Forexample, different isotopic forms of hydrogen (H) include protium (¹H)and deuterium (²H). Protium is the predominant hydrogen isotope found innature. Enriching for deuterium may afford certain therapeuticadvantages, such as increasing in vivo half-life or reducing dosagerequirements, or may provide a compound useful as a standard forcharacterization of biological samples. Isotopically-enriched compoundsof the invention can be prepared without undue experimentation byconventional techniques well known to those skilled in the art or byprocesses analogous to those described in the schemes and examplesherein using appropriate isotopically-enriched reagents and/orintermediates.

Those skilled in the art will recognize those instances in which thecompounds of the invention may form salts. In such instances, anotherembodiment provides pharmaceutically acceptable salts of the compoundsof the invention. Thus, reference to a compound of the invention hereinis understood to include reference to salts thereof, unless otherwiseindicated. The term “pharmaceutically acceptable salts” refers to saltsprepared from pharmaceutically acceptable non-toxic bases or acidsincluding inorganic or organic bases and inorganic or organic acids. Inaddition, when a compound of the invention contains both a basic moiety,such as, but not limited to a pyridine or imidazole, and an acidicmoiety, such as, but not limited to a carboxylic acid, zwitterions(“inner salts”) may be formed and are included within the presentinvention. Salts derived from inorganic bases include aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganicsalts, manganous, potassium, sodium, zinc, and the like. Particularembodiments include the ammonium, calcium, magnesium, potassium, andsodium salts. Salts in the solid form may exist in more than one crystalstructure, and may also be in the form of hydrates or solvates. Saltsderived from pharmaceutically acceptable organic non-toxic bases includesalts of primary, secondary, and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines, andbasic ion exchange resins, such as arginine, betaine, caffeine, choline,N,N′-dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine,histidine, hydrabamine, isopropylamine, lysine, methylglucamine,morpholine, piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine,tromethamine, and the like. When the compound of the present inventionis basic, salts may be prepared from pharmaceutically acceptablenon-toxic acids, including inorganic and organic acids. Such acidsinclude acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,p-toluenesulfonic acid, and the like. Particular embodiments include thecitric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric,trifluoroacetic, fumaric, and tartaric acids. It will be understoodthat, as used herein, references to the compounds of Formula I are meantto also include the pharmaceutically acceptable salts. Salts of thecompounds of the invention may be formed by methods known to those ofordinary skill in the art, for example, by reacting a compound of theinvention with an amount of acid or base, such as an equivalent amount,in a medium such as one in which the salt precipitates or in an aqueousmedium followed by lyophilization.

Exemplifying the invention is the use of the compounds disclosed in theExamples and herein. Specific compounds within the present inventioninclude a compound which is selected from the compounds disclosed in thefollowing Examples and pharmaceutically acceptable salts thereof andindividual enantiomers or diastereomers thereof.

The subject compounds may be useful in a method of treating acardiovascular or cerebrovascular disease, or a neurological orpsychiatric disorder associated with PDE9 dysfunction in a patient suchas a mammal in need of such inhibition comprising the administration ofan effective amount of the compound. In addition to primates, especiallyhumans, a variety of other mammals may be treated according to themethod of the present invention. The subject compounds may be useful ina method of inhibiting PDE9 activity in a patient such as a mammal inneed of such inhibition comprising the administration of an effectiveamount of the compound. The subject compounds may also may be useful fortreating a neurological or psychiatric disorder associated with striatalhypofunction or basal ganglia dysfunction in a mammalian patient in needthereof. The subject compounds may also may be useful for treating acardiovascular and cerebrovascular disease, such as hypertension andheart failure. In addition to primates, especially humans, a variety ofother mammals may be treated according to the method of the presentinvention.

The present invention is directed to a compound of the present inventionor a pharmaceutically acceptable salt thereof for use in medicine. Thepresent invention is further directed to a use of a compound of thepresent invention or a pharmaceutically acceptable salt thereof for themanufacture of a medicament for treating a neurological or psychiatricdisorder associated with PDE9 dysfunction in a mammalian patient in needthereof. The present invention is further directed to a use of acompound of the present invention or a pharmaceutically acceptable saltthereof for the manufacture of a medicament for treating neurologicaland psychiatric disorders, such as schizophrenia, psychosis orHuntington's disease, and those associated with striatal hypofunction orbasal ganglia dysfunction, and cardiovascular and cerebrovasculardiseases, such as hypertension and heart failure, in a mammalian patientin need thereof.

As used herein, the terms “treatment” and “treating” refer to processeswherein there may be a slowing, interrupting, arresting, controlling, orstopping of the progression of the diseases or disorders describedherein, but does not necessarily indicate a total elimination of alldisease or disorder symptoms, as well as the prophylactic therapy toretard the progression or reduce the risk of the noted conditions,particularly in a patient who is predisposed to such disease ordisorder, but does not yet experience or display symptoms of the diseasestate, inhibiting the disease state, i.e., arresting the development ofthe disease state or its clinical symptoms, or relieving the diseasestate, i.e., causing temporary or permanent regression of the diseasestate or its clinical symptoms.

The subject treated in the present methods is generally a mammal, inparticular, a human being, male or female, in whom therapy is desired.The term “therapeutically effective amount” means the amount of thesubject compound that will elicit the biological or medical response ofa tissue, system, animal or human that is being sought by theresearcher, veterinarian, medical doctor or other clinician. It isrecognized that one skilled in the art may affect the neurological andpsychiatric disorders by treating a patient presently afflicted with thedisorders or by prophylactically treating a patient afflicted with suchdisorders with an effective amount of the compound of the presentinvention.

Inhibitors of PDE9, and in particular inhibitors of PDE9A, may providetherapeutic benefit to those individuals suffering from psychiatric andcognitive disorders. The conserved localization of PDE9 in cortex andhippocampus of rodents and humans, brain regions that play a key role inmemory and learning, together with the previously described role forNO/cGMP/PKG signaling in synaptic plasticity and cognition has focusedattention on a possible role for PDE9 in cognitive function andconsequently as a therapeutic target for cognitive dysfunction inAlzheimer's disease and schizophrenia. The mechanism by which PDE9inhibition improve cognitive function through the modulation ofglutamate and/or cholinergic neuron signaling is potentially feasiblegiven that both glutamate (NMDA) and cholinergic receptor activationenhance the formation of cGMP in brain and both neural substrates areinvolved in cognitive function.

As used herein, the term “selective PDE9 inhibitor” refers to an organicmolecule that effectively inhibits an enzyme from the PDE9 family to agreater extent than enzymes from the PDE 1-8 or PDE10-11 families. Inone embodiment, a selective PDE9 inhibitor is an organic molecule havinga Ki for inhibition of PDE9 that is less than or about one-tenth thatfor a substance that is an inhibitor for another PDE enzyme. In otherwords, the organic molecule inhibits PDE9 activity to the same degree ata concentration of about one-tenth or less than the concentrationrequired for any other PDE enzyme. Preferably, a selective PDE9inhibitor is an organic molecule, having a Ki for inhibition of PDE9that is less than or about one-hundredth that for a substance that is aninhibitor for another PDE enzyme. In other words, the organic moleculeinhibits PDE9 activity to the same degree at a concentration of aboutone-hundredth or less than the concentration required for any other PDEenzyme. A “selective PDE9 inhibitor” can be identified, for example, bycomparing the ability of an organic molecule to inhibit PDE9 activity toits ability to inhibit PDE enzymes from the other PDE families. Forexample, an organic molecule may be assayed for its ability to inhibitPDE9 activity, as well as PDE1A, PDE1B, PDE1C, PDE2A, PDE3A, PDE3B,PDE4A, PDE4B, PDE4C, PDE4D, PDE5A, PDE6A, PDE6B, PDE6C, PDE7A, PDE7B,PDE8A, PDE8B, PDE10A, and/or PDE11A.

Phosphodiesterase enzymes including PDE9 have been implicated in a widerange of biological functions. This has suggested a potential role forthese enzymes in a variety of disease processes in humans or otherspecies. The compounds of the present invention may have utility intreating a variety of neurological and psychiatric disorders, such asschizophrenia, psychosis or Huntington's disease, and those associatedwith striatal hypofunction or basal ganglia dysfunction, andcardiovascular and cerebrovascular diseases, such as hypertension andheart failure.

In an embodiment, compounds of the present invention may provide amethod for treating schizophrenia or psychosis comprising administeringto a patient in need thereof an effective amount of a compound of thepresent invention. The Diagnostic and Statistical Manual of MentalDisorders (DSM-IV-TR) (2000, American Psychiatric Association,Washington D.C.) provides a diagnostic tool that includes paranoid,disorganized, catatonic or undifferentiated schizophrenia andsubstance-induced psychotic disorders. As used herein, the term“schizophrenia or psychosis” includes the diagnosis and classificationof these mental disorders as described in DSM-IV-TR and the term isintended to include similar disorders described in other sources.Disorders and conditions encompassed herein include, but are not limitedto, conditions or diseases such as schizophrenia or psychosis, includingschizophrenia (paranoid, disorganized, catatonic, undifferentiated, orresidual type), schizophreniform disorder, schizoaffective disorder, forexample of the delusional type or the depressive type, delusionaldisorder, psychotic disorder, brief psychotic disorder, shared psychoticdisorder, psychotic disorder due to a general medical condition andsubstance-induced or drug-induced (for example psychosis induced byalcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants,opioids, phencyclidine, ketamine and other dissociative anaesthetics,and other psychostimulants), psychosispsychotic disorder, psychosisassociated with affective disorders, brief reactive psychosis,schizoaffective psychosis, “schizophrenia-spectrum” disorders such asschizoid or schizotypal personality disorders, personality disorder ofthe paranoid type, personality disorder of the schizoid type, illnessassociated with psychosis (such as major depression, manic depressive(bipolar) disorder, Alzheimer's disease and post-traumatic stresssyndrome), including both the positive and the negative symptoms ofschizophrenia and other psychoses.

In another embodiment, the compounds of the present invention mayprovide a method for treating cognitive disorders or enhancing cognitioncomprising administering to a patient in need thereof an effectiveamount of a compound of the present invention. The DSM-IV-TR alsoprovides a diagnostic tool that includes cognitive disorders includingdementia, delirium, amnestic disorders and age-related cognitivedecline. As used herein, the term “cognitive disorders” includes thediagnosis and classification of these disorders as described inDSM-IV-TR and the term is intended to include similar disordersdescribed in other sources. Disorders and conditions encompassed hereininclude, but are not limited to, disorders that comprise as a symptom adeficiency in attention and/or cognition, such as dementia (associatedwith Alzheimer's disease, ischemia, multi-infarct dementia, trauma,intracranial tumors, cerebral trauma, vascular problems or stroke,alcoholic dementia or other drug-related dementia, AIDS, HIV disease,Parkinson's disease, Huntington's disease, Pick's disease, CreutzfeldtJacob disease, perinatal hypoxia, other general medical conditions orsubstance abuse), Alzheimer's disease, multi-infarct dementia,AIDS-related dementia, and Fronto temperal dementia, delirium, amnesticdisorders or age related cognitive decline.

In another embodiment, compounds of the present invention may provide amethod for treating anxiety disorders comprising administering to apatient in need thereof an effective amount of a compound of the presentinvention. The DSM-IV-TR also provides a diagnostic tool that includesanxiety disorders as generalized anxiety disorder, obsessive-compulsivedisorder and panic attack. As used herein, the term “anxiety disorders”includes the diagnosis and classification of these mental disorders asdescribed in DSM-IV-TR and the term is intended to include similardisorders described in other sources. Disorders and conditionsencompassed herein include, but are not limited to, anxiety disorderssuch as, acute stress disorder, agoraphobia, generalized anxietydisorder, obsessive-compulsive disorder, panic attack, panic disorder,post-traumatic stress disorder, separation anxiety disorder, socialphobia, specific phobia, substance-induced anxiety disorder and anxietydue to a general medical condition.

In another embodiment, compounds of the present invention may provide amethod for treating substance-related disorders and addictive behaviorscomprising administering to a patient in need thereof an effectiveamount of a compound of the present invention. The DSM-IV-TR alsoprovides a diagnostic tool that includes persisting dementia, persistingamnestic disorder, psychotic disorder or anxiety disorder induced bysubstance abuse, and tolerance of, dependence on or withdrawal fromsubstances of abuse. As used herein, the term “substance-relateddisorders and addictive behaviors” includes the diagnosis andclassification of these mental disorders as described in DSM-IV-TR andthe term is intended to include similar disorders described in othersources. Disorders and conditions encompassed herein include, but arenot limited to, substance-related disorders and addictive behaviors,such as substance-induced delirium, persisting dementia, persistingamnestic disorder, psychotic disorder or anxiety disorder, drugaddiction, tolerance, and dependence or withdrawal from substancesincluding alcohol, amphetamines, cannabis, cocaine, hallucinogens,inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics oranxiolytics.

In another embodiment, compounds of the present invention may provide amethod for treating obesity or eating disorders associated withexcessive food intake, and complications associated therewith,comprising administering to a patient in need thereof an effectiveamount of a compound of the present invention. At present, obesity isincluded in the tenth edition of the International Classification ofDiseases and Related Health Problems (ICD-10) (1992 World HealthOrganization) as a general medical condition. The DSM-IV-TR alsoprovides a diagnostic tool that includes obesity in the presence ofpsychological factors affecting medical condition. As used herein, theterm “obesity or eating disorders associated with excessive food intake”includes the diagnosis and classification of these medical conditionsand disorders described in ICD-10 and DSM-IV-TR and the term is intendedto include similar disorders described in other sources. Disorders andconditions encompassed herein include, but are not limited to, obesity,bulimia nervosa and compulsive eating disorders.

In another embodiment, compounds of the present invention may provide amethod for treating mood and depressive disorders comprisingadministering to a patient in need thereof an effective amount of acompound of the present invention. As used herein, the term “mood anddepressive disorders” includes the diagnosis and classification of thesemedical conditions and disorders described in the DSM-IV-TR and the termis intended to include similar disorders described in other sources.Disorders and conditions encompassed herein include, but are not limitedto, bipolar disorders, mood disorders including depressive disorders,major depressive episode of the mild, moderate or severe type, a manicor mixed mood episode, a hypomanic mood episode, a depressive episodewith atypical features, a depressive episode with melancholic features,a depressive episode with catatonic features, a mood episode withpostpartum onset, post-stroke depression; major depressive disorder,dysthymic disorder, minor depressive disorder, premenstrual dysphoricdisorder, post-psychotic depressive disorder of schizophrenia, a majordepressive disorder superimposed on a psychotic disorder such asdelusional disorder or schizophrenia, a bipolar disorder, for example,bipolar I disorder, bipolar II disorder, cyclothymic disorder,depression including unipolar depression, seasonal depression andpost-partum depression, premenstrual syndrome (PMS) and premenstrualdysphoric disorder (PDD), mood disorders due to a general medicalcondition, and substance-induced mood disorders.

In another embodiment, compounds of the present invention may provide amethod for treating pain comprising administering to a patient in needthereof an effective amount of a compound of the present invention.Particular pain embodiments are bone and joint pain (osteoarthritis),repetitive motion pain, dental pain, cancer pain, myofascial pain(muscular injury, fibromyalgia), perioperative pain (general surgery,gynecological), chronic pain and neuropathic pain.

In other embodiments, compounds of the invention may provide methods fortreating other types of cognitive, learning and mental related disordersincluding, but not limited to, learning disorders, such as a readingdisorder, a mathematics disorder, or a disorder of written expression,attention-deficit/hyperactivity disorder, age-related cognitive decline,pervasive developmental disorder including autistic disorder, attentiondisorders such as attention-deficit hyperactivity disorder (ADHD) andconduct disorder; an NMDA receptor-related disorder, such as autism,depression, benign forgetfulness, childhood learning disorders andclosed head injury; a neurodegenerative disorder or condition, such asneurodegeneration associated with cerebral trauma, stroke, cerebralinfarct, epileptic seizure, neurotoxin poisoning, orhypoglycemia-induced neurodegeneration; multi-system atrophy; movementdisorders, such as akinesias and akinetic-rigid syndromes (including,Parkinson's disease, drug-induced parkinsonism, post-encephaliticparkinsonism, progressive supranuclear palsy, multiple system atrophy,corticobasal degeneration, parkinsonism-ALS dementia complex and basalganglia calcification), medication-induced parkinsonism (such as,neuroleptic-induced parkinsonism, neuroleptic malignant syndrome,neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia,neuroleptic-induced tardive dyskinesia and medication-induced posturaltremor), Huntington's disease, dyskinesia associated with dopamineagonist therapy, Gilles de la Tourette's syndrome, epilepsy, muscularspasms and disorders associated with muscular spasticity or weaknessincluding tremors; dyskinesias, including tremor (such as, rest tremor,postural tremor, intention tremor and essential tremor), restless legsyndrome, chorea (such as Sydenham's chorea, Huntington's disease,benign hereditary chorea, neuroacanthocytosis, symptomatic chorea,drug-induced chorea and hemiballism), myoclonus (including, generalisedmyoclonus and focal myoclonus), tics (including, simple tics, complextics and symptomatic tics), dystonia (including, generalised,iodiopathic, drug-induced, symptomatic, paroxymal, and focal (such asblepharospasm, oromandibular, spasmodic, spasmodic torticollis, axialdystonia, hemiplegic and dystonic writer's cramp)); urinaryincontinence; neuronal damage (including ocular damage, retinopathy ormacular degeneration of the eye, tinnitus, hearing impairment and loss,and brain edema); emesis; and sleep disorders, including insomnia andnarcolepsy.

In another embodiment, compounds of the present invention may provide amethod for treating hypertension, such as essential hypertension (alsoknown as primary or idiopathic hypertension) which is a form ofhypertension for which no cause can be found, systemic hypertension,pulmonary hypertension (e.g. pulmonary arterial hypertension, pulmonaryhypertension of the neonate), and heart failure (which includes bothacute heart failure and chronic heart failure, the latter also known ascongestive heart failure). The compounds could also be used to treathypertension which is associated with any of several primary diseases,such as renal, pulmonary, endocrine, and vascular diseases, includingtreatment of patients with medical conditions such as heart failureand/or chronic kidney disease. Furthermore, the compounds of the presentinvention could be used in methods for treatment of, prevention of orreduction of risk for developing one or more disorders such as pulmonaryhypertension, particularly pulmonary arterial hypertension,cardiovascular disease, edematous states, diabetes mellitus, diabetesinsipidus, post-operative volume overload, endothelial dysfunction,diastolic dysfunction, systolic dysfunction, stable and unstable anginapectoris, thromboses, restenosis, myocardial infarction, stroke, cardiacinsufficiency, pulmonary hypertonia, atherosclerosis, hepatic cirrhosis,ascitis, pre-eclampsia, cerebral edema, nephropathy, glomerulonephritis,nephrotic syndrome, acute kidney insufficiency, chronic kidneyinsufficiency (also referred to as chronic kidney disease, or moregenerally as renal impairment), acute tubular necrosis, hypercalcemia,idiopathic edema, Dent's disease, Meniere's disease, glaucoma, benignintracranial hypertension, and other conditions.

In a specific embodiment, compounds of the present invention may providea method for treating thrombosis, atherosclerosis, restenosis,hypertension, angina pectoris, angiogenesis related disorders,arrhythmia, a cardiovascular or circulatory disease or condition, acutecoronary syndrome, coronary artery disease, thrombosis, conditions ofreduced blood vessel patency (for example post percutaneous transluminalcoronary angioplasty), peripheral vascular disease, renal disease(especially that occurring with diabetes), angina (including stable,unstable and variant (Prinzmetal) angina), myocardial ischaemia,myocardial infarction, secondary prevention of myocardial infarction orstroke, urgent coronary revascularization, glomerulonephritis,thrombotic stroke, thromboembolytic stroke, peripheral artery disease,deep vein thrombosis, venous thromboembolism, cardiovascular diseaseassociated with hormone replacement therapy, atherosclerosis,hypercholesterolemia, coronary heart disease, metabolic syndrome, acutecoronary syndrome, disseminated intravascular coagulation syndrome,cerebral infarction, and conditions associated with cardiopulmonarybypass surgery, cardiac valve repair and replacement surgery,pericardial and aortic repair surgeries, such as bleeding, thromboticvascular events (such as thrombosis or restenosis), vein graft failure,artery graft failure, atherosclerosis, angina pectoris, myocardialischemia, acute coronary syndrome, myocardial infarction, heart failure,arrhythmia, hypertension, transient ischemic attack, cerebral functionimpairment, thromboembolic stroke, cerebral ischemia, cerebralinfarction, thrombophlebitis, deep vein thrombosis and peripheral arterydisease.

Of the disorders above, the treatment of schizophrenia, bipolardisorder, depression, including unipolar depression, seasonal depressionand post-partum depression, premenstrual syndrome (PMS) and premenstrualdysphoric disorder (PDD), learning disorders, pervasive developmentaldisorders, including autistic disorder, attention disorders includingAttention-Deficit/Hyperactivity Disorder, autism, tic disordersincluding Tourette's disorder, anxiety disorders including phobia andpost traumatic stress disorder, cognitive disorders associated withdementia, AIDS dementia, Alzheimer's, Parkinson's, Huntington's disease,spasticity, myoclonus, muscle spasm, tinnitus and hearing impairment andloss are of particular importance.

The activity of the compounds in accordance with the present inventionas PDE9 inhibitors may be readily determined without undueexperimentation using a fluorescence polarization (FP) methodology thatis well known in the art (Huang, W., et al., J. Biomol Screen, 2002, 7:215). In particular, the compounds of the following examples hadactivity in reference assays by exhibiting the ability to inhibit thehydrolysis of the phosphosphate ester bond of a cyclic nucleotide.

In a typical experiment the PDE9 inhibitory activity of the compounds ofthe present invention was determined in accordance with the followingexperimental method.

Human PDE9 (PDE9A2, GenBank Accession No. NM 001001567), full lengthwith N-terminal GST tag, was purchased from BPS Bioscience. Thefluorescence polarization assay for cyclic nucleotide phosphodiesteraseswas performed using an IMAP® FP kit supplied by Molecular Devices,Sunnyvale, Calif. (product # R8139). IMAP® technology has been appliedpreviously to phosphodiesterase assays (Huang, W., et al., J. BiomolScreen, 2002, 7: 215). Assays were performed at room temperature in384-well microtiter plates with an incubation volume of 20.2 μL.Solutions of test compounds were prepared in DMSO and serially dilutedwith DMSO to yield 8 μL of each of 10 solutions differing by 3-fold inconcentration, at 32 serial dilutions per plate. 100% inhibition isdetermined using a known PDE9 inhibitor, such as1-(2-chlorophenyl)-6-[(2R)-3,3,3-trifluoro-2-methylpropyl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one(BAY 73-6691) (Wunder et al, Mol. Pharmacol., 2005, 68(6): 1775-81),(6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one(PF-04447943) (Wager et al., ACS Chemical Neuroscience, 2010,1:435-449). 0% of inhibition is determined by using DMSO (1% finalconcentrations). A Labcyte Echo 555 (Labcyte, Sunnyvale, Calif.) is usedto dispense 200 nL from each well of the titration plate to the 384 wellassay plate. Human PDE9A2 membrane preps were diluted to 1 ng/ml.FAM-labeled cGMP substrate (Molecular Devices, Sunnyvale, Calif.) was ata concentration of 100 nM (Km of PDE9 for cGMP is 70-170 nM) in theassay buffer (10 mM Tris HCl, pH 7.2, 10 mM MgCl₂, 0.05% NaN₃ 0.01%Tween-20, and 1 mM DTT). PDE9 enzyme mix and compounds were mixed andincubated at room temperature for 30 min. Following which, FAMcGMPsubstrate was added, shaken and incubated for an additional 60 min atroom temperature. The final concentration of human PDE9 membranepreparations were 0.5 ng/ml. The final concentration of FAM-cGMP was 50nM. After the incubation period, the enzymatic reaction was stopped byaddition of binding solution (IMAP-FP, Molecular Devices, comprised of80% Solution A, 20% Solution B and a 1:600 dilution of binding reagent)to each well. The plates were shaken then incubated at room temperaturefor 1 h prior to determining the fluorescence polarization (mP) using aPerkin Elmer EnVision™ plate reader (Waltham, Mass.).

Fluorescence polarization (mP) was calculated from the parallel (S) andperpendicular (P) fluorescence of each sample well and the analogousvalues for the median control well, containing only substrate (So andPo), using the following equation:

Polarization (mP)=1000*(S/So−P/Po)/(S/So+P/Po).

Dose-inhibition profiles for each compound were characterized by fittingthe mP data to a four-parameter equation given below. The apparentinhibition constant (K_(I)) the maximum inhibition at the low plateaurelative to “100% Inhibition Control” (Imax; e.g. 1=>same as thiscontrol), the minimum inhibition at the high plateau relative to the “0%Inhibition Control” (Imin, e.g. 0=>same as the no drug control) and theHill slope (nH) are determined by a non-linear least squares fitting ofthe mP values as a function of dose of the compound using an in-housesoftware based on the procedures described by Mosser et al., JALA, 2003,8: 54-63, using the following equation:

${mP} = {\frac{\left( {{0\% \mspace{20mu} {mP}} - {100\% \mspace{14mu} {mP}}} \right)\left( {{I\; \max} - {I\; \min}} \right)}{1 + \left\lbrack \frac{\lbrack{Drug}\rbrack}{\left( {10^{- {pK}_{I}}\left( {1 + \frac{\lbrack{Substrate}\rbrack}{K_{M}}} \right)} \right.} \right\rbrack^{nH}} + {100\% \mspace{14mu} {mP}} + {\left( {{0\% \mspace{14mu} {mP}} - {100\% \mspace{14mu} {mP}}} \right)\left( {1 - {I\; \max}} \right)}}$

The median signal of the “0% inhibition controls” (0% mP) and the mediansignal of the “100% inhibition controls” (100% mP) are constantsdetermined from the controls located in columns 1-2 and 23-24 of eachassay plate. An apparent (K_(m)) for FAM-labeled cAMP of 150 nM wasdetermined in separate experiments through simultaneous variation ofsubstrate and selected drug concentrations.

Selectivity for PDE9, as compared to other PDE families, was assessedusing the IMAP® technology. Human PDE10A2 enzyme was prepared fromcytosolic fractions of transiently transfected HEK cells. All otherPDE's were GST Tag human enzyme expressed in insect cells and wereobtained from BPS Bioscience (San Diego, Calif.): PDE1A (Cat #60010),PDE3A (Cat #60030), PDE4A1A (Cat #60040), PDE5A1 (Cat #60050), PDE6C(Cat #60060), PDE7A (Cat #60070), PDE8A1 (Cat #60080), PDE9A2 (Cat#60090), PDE11A4 (Cat #60110).

Assays for PDE 1 through 11 were performed in parallel at roomtemperature in 384-well microtiter plates with an incubation volume of20.2 μL. Solutions of test compounds were prepared in DMSO and seriallydiluted with DMSO to yield 30 μL of each of ten solutions differing by3-fold in concentration, at 32 serial dilutions per plate. 100%inhibition was determined by adding buffer in place of the enzyme and 0%inhibition is determined by using DMSO (1% final concentrations). ALabcyte POD 810 (Labcyte, Sunnyvale, Calif.) was used to dispense 200 nLfrom each well of the titration plate to make eleven copies of the assayplate for each titration, one copy for each PDE enzyme. A solution ofeach enzyme (dilution from aliquots, sufficient to produce 20% substrateconversion) and a separate solution of FAM-labeled cAMP or FAM-labeledcGMP from Molecular Devices (Sunnyvale, Calif., product # R7506 or cGMP# R7508), at a final concentration of 50 nM were made in the assaybuffer (10 mM Tris HCl, pH 7.2, 10 mM MgCl₂, 0.05% NaN₃ 0.01% Tween-20,and 1 mM DTT). Note that the substrate for PDE2 is 50 nM FAM cAMPcontaining 1000 nM of cGMP. The enzyme and the substrate were then addedto the assay plates in two consecutive additions of 10 μL and thenshaken to mix. The reaction was allowed to proceed at room temperaturefor 60 minutes. A binding solution was then made from the kitcomponents, comprised of 80% Solution A, 20% Solution B and bindingreagent at a volume of 1/600 the total binding solution. The enzymaticreaction was stopped by addition of 60 μL of the binding solution toeach well of the assay plate. The plates were sealed and shaken for 10seconds. The plates were incubated at room temperature for one hour. Theparallel and perpendicular fluorescence of each well of the plate wasmeasured using a Perkin Elmer EnVision™ plate reader (Waltham, Mass.).

The apparent inhibition constants for the compounds against all 11 PDE'swas determined from the parallel and perpendicular fluorescent readingsas described for PDE FP assay using the following apparent K_(M) valuesfor each enzyme and substrate combination: PDE1A (FAM cGMP) 70 nM,rhesus PD2A3 (FAM cAMP) 10,000 nM, PDE3A (FAM cAMP) 50 nM, PDE4A1A (FAMcAMP) 1500 nM, PDE5A1 (FAM cGMP) 400 nM, PDE6C (FAM cGMP) 700 nM, PDE7A(FAM cAMP) 150 nM, PDE8A1 (FAM cAMP) 50 nM, PDE10A2 (FAM cAMP) 150 nM,PDE11A4 (FAM cAMP) 1000 nM. The intrinsic PDE10 inhibitory activity of acompound which may be used in accordance with the present invention maybe determined by these assays.

The compounds of the following examples had activity in inhibiting thehuman PDE9 enzyme in the aforementioned assays, generally with a Ki ofless than about 500 nM. Many of compounds within the present inventionhad activity in inhibiting the human PDE9 enzyme in the aforementionedassays with a Ki of less than about 100 nM, and wherein some of thecompounds have a Ki of less than about 10 nM. Additional data areprovided in the following Examples. Such a result is indicative of theintrinsic activity of the compounds in use as inhibitors of the PDE9enzyme. In general, one of ordinary skill in the art would appreciatethat a substance is considered to effectively inhibit PDE9 activity ifit has a Ki of less than or about 500 nM, where more potent inhibitorshave a Ki of less than or about 100 nM. The present invention alsoincludes compounds within the scope of the invention which possessactivity as inhibitors of other phosphodiesterase enzymes.

The subject compounds may be further useful in a method for theprevention, treatment, control, amelioration, or reduction of risk ofthe diseases, disorders and conditions noted herein. The subjectcompounds may be further useful in a method for the prevention,treatment, control, amelioration, or reduction of risk of theaforementioned diseases, disorders and conditions in combination withother agents. The compounds of the present invention may be used incombination with one or more other drugs in the treatment, prevention,control, amelioration, or reduction of risk of diseases or conditionsfor which compounds of the present invention or the other drugs may haveutility, where the combination of the drugs together are safer or moreeffective than either drug alone. Such other drug(s) may beadministered, by a route and in an amount commonly used therefore,contemporaneously or sequentially with a compound of the presentinvention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition in unit dosage form containing such other drugs and thecompound of the present invention may be desirable. However, thecombination therapy may also include therapies in which the compound ofthe present invention and one or more other drugs are administered ondifferent overlapping schedules. It is also contemplated that when usedin combination with one or more other active ingredients, the compoundsof the present invention and the other active ingredients may be used inlower doses than when each is used singly. Accordingly, thepharmaceutical compositions of the present invention include those thatcontain one or more other active ingredients, in addition to a compoundof the present invention. The above combinations include combinations ofa compound of the present invention not only with one other activecompound, but also with two or more other active compounds. Likewise,compounds of the present invention may be used in combination with otherdrugs that are used in the prevention, treatment, control, amelioration,or reduction of risk of the diseases or conditions for which compoundsof the present invention are useful. Such other drugs may beadministered, by a route and in an amount commonly used therefore,contemporaneously or sequentially with a compound of the presentinvention. Accordingly, the pharmaceutical compositions of the presentinvention include those that also contain one or more other activeingredients, in addition to a compound of the present invention. Theweight ratio of the compound of the present invention to the secondactive ingredient may be varied and will depend upon the effective doseof each ingredient. Generally, an effective dose of each will be used.Thus, for example, when a compound of the present invention is combinedwith another agent, the weight ratio of the compound of the presentinvention to the other agent will generally range from about 1000:1 toabout 1:1000, such as about 200:1 to about 1:200. Combinations of acompound of the present invention and other active ingredients willgenerally also be within the aforementioned range, but in each case, aneffective dose of each active ingredient should be used.

In such combinations the compound of the present invention and otheractive agents may be administered separately or in conjunction. Inaddition, the administration of one element may be prior to, concurrentto, or subsequent to the administration of other agent(s).

Accordingly, the subject compounds may be used alone or in combinationwith other agents which are known to be beneficial in the subjectindications or other drugs that affect receptors or enzymes that eitherincrease the efficacy, safety, convenience, or reduce unwanted sideeffects or toxicity of the compounds of the present invention. Thesubject compound and the other agent may be co-administered, either inconcomitant therapy or in a fixed combination.

In one embodiment, the subject compound may be employed in combinationwith anti-Alzheimer's agents, beta-secretase inhibitors, gamma-secretaseinhibitors, HMG-CoA reductase inhibitors, NSAID's including ibuprofen,vitamin E, and anti-amyloid antibodies.

In another embodiment, the subject compound may be employed incombination with sedatives, hypnotics, anxiolytics, antipsychotics,antianxiety agents, cyclopyrrolones, imidazopyridines,pyrazolopyrimidines, minor tranquilizers, melatonin agonists andantagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2antagonists, and the like, such as: adinazolam, allobarbital, alonimid,alprazolam, amisulpride, amitriptyline, amobarbital, amoxapine,aripiprazole, atypical antipsychotics, bentazepam, benzoctamine,brotizolam, bupropion, busprione, butabarbital, butalbital, capuride,carbocloral, chloral betaine, chloral hydrate, clomipramine, clonazepam,cloperidone, clorazepate, chlordiazepoxide, clorethate, chlorpromazine,clozapine, cyprazepam, desipramine, dexclamol, diazepam,dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam,ethchlorvynol, etomidate, fenobam, flunitrazepam, flupentixol,fluphenazine, flurazepam, fluvoxamine, fluoxetine, fosazepam,glutethimide, halazepam, haloperidol, hydroxyzine, imipramine, lithium,lorazepam, lormetazepam, maprotiline, mecloqualone, melatonin,mephobarbital, meprobamate, methaqualone, midaflur, midazolam,nefazodone, nisobamate, nitrazepam, nortriptyline, olanzapine, oxazepam,paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine,phenelzine, phenobarbital, prazepam, promethazine, propofol,protriptyline, quazepam, quetiapine, reclazepam, risperidone,roletamide, secobarbital, sertraline, suproclone, temazepam,thioridazine, thiothixene, tracazolate, tranylcypromaine, trazodone,triazolam, trepipam, tricetamide, triclofos, trifluoperazine,trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon,ziprasidone, zolazepam, zolpidem, and salts thereof, and combinationsthereof, and the like, or the subject compound may be administered inconjunction with the use of physical methods such as with light therapyor electrical stimulation.

In another embodiment, the subject compound may be employed incombination with levodopa (with or without a selective extracerebraldecarboxylase inhibitor such as carbidopa or benserazide),anticholinergics such as biperiden (optionally as its hydrochloride orlactate salt) and trihexyphenidyl (benzhexol) hydrochloride, COMTinhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2aadenosine receptor antagonists, cholinergic agonists, NMDA receptorantagonists, serotonin receptor antagonists and dopamine receptoragonists such as alentemol, bromocriptine, fenoldopam, lisuride,naxagolide, pergolide and pramipexole. It will be appreciated that thedopamine agonist may be in the form of a pharmaceutically acceptablesalt, for example, alentemol hydrobromide, bromocriptine mesylate,fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate.Lisuride and pramipexol are commonly used in a non-salt form.

In another embodiment, the subject compound may be employed incombination with a compound from the phenothiazine, thioxanthene,heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine andindolone classes of neuroleptic agent. Suitable examples ofphenothiazines include chlorpromazine, mesoridazine, thioridazine,acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitableexamples of thioxanthenes include chlorprothixene and thiothixene. Anexample of a dibenzazepine is clozapine. An example of a butyrophenoneis haloperidol. An example of a diphenylbutylpiperidine is pimozide. Anexample of an indolone is molindolone. Other neuroleptic agents includeloxapine, sulpiride and risperidone. It will be appreciated that theneuroleptic agents when used in combination with the subject compoundmay be in the form of a pharmaceutically acceptable salt, for example,chlorpromazine hydrochloride, mesoridazine besylate, thioridazinehydrochloride, acetophenazine maleate, fluphenazine hydrochloride,flurphenazine enathate, fluphenazine decanoate, trifluoperazinehydrochloride, thiothixene hydrochloride, haloperidol decanoate,loxapine succinate and molindone hydrochloride. Perphenazine,chlorprothixene, clozapine, haloperidol, pimozide and risperidone arecommonly used in a non-salt form. Thus, the subject compound may beemployed in combination with acetophenazine, alentemol, aripiprazole,amisulpride, benzhexol, bromocriptine, biperiden, chlorpromazine,chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine,haloperidol, levodopa, levodopa with benserazide, levodopa withcarbidopa, lisuride, loxapine, mesoridazine, molindolone, naxagolide,olanzapine, pergolide, perphenazine, pimozide, pramipexole, quetiapine,risperidone, sulpiride, tetrabenazine, trihexyphenidyl, thioridazine,thiothixene, trifluoperazine or ziprasidone.

In another embodiment, the subject compound may be employed incombination with an anti-depressant or anti-anxiety agent, includingnorepinephrine reuptake inhibitors (including tertiary amine tricyclicsand secondary amine tricyclics), selective serotonin reuptake inhibitors(SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors ofmonoamine oxidase (RIMAs), serotonin and noradrenaline reuptakeinhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists,α-adrenoreceptor antagonists, neurokinin-1 receptor antagonists,atypical anti-depressants, benzodiazepines, 5-HT_(1A) agonists orantagonists, especially 5-HT_(1A) partial agonists, and corticotropinreleasing factor (CRF) antagonists. Specific agents include:amitriptyline, clomipramine, doxepin, imipramine and trimipramine;amoxapine, desipramine, maprotiline, nortriptyline and protriptyline;fluoxetine, fluvoxamine, paroxetine and sertraline; isocarboxazid,phenelzine, tranylcypromine and selegiline; moclobemide: venlafaxine;duloxetine; aprepitant; bupropion, lithium, nefazodone, trazodone andviloxazine; alprazolam, chlordiazepoxide, clonazepam, chlorazepate,diazepam, halazepam, lorazepam, oxazepam and prazepam; buspirone,flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptablesalts thereof.

In one embodiment, the subject compound may be employed in combinationwith thiazide-like diuretics, e.g., hydrochlorothiazide (HCTZ or HCT);angiotensin converting enzyme inhibitors (e.g, alacepril, benazepril,captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat,fosinopril, imidapril, lisinopril, moveltipril, perindopril, quinapril,ramipril, spirapril, temocapril, or trandolapril); dual inhibitors ofangiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) suchas omapatrilat, sampatrilat and fasidotril; angiotensin II receptorantagonists, also known as angiotensin receptor blockers or ARBs, whichmay be in free-base, free-acid, salt or pro-drug form, such asazilsartan, e.g., azilsartan medoxomil potassium (EDARBI®), candesartan,e.g., candesartan cilexetil (ATACAND®), eprosartan, e.g., eprosartanmesylate (TEVETAN®), irbesartan (AVAPRO®), losartan, e.g., losartanpotassium (COZAAR®), olmesartan, e.g, olmesartan medoximil (BENICAR®),telmisartan (MICARDIS®), valsartan (DIOVAN®), and any of these drugsused in combination with a thiazide-like diuretic such ashydrochlorothiazide (e.g., HYZAAR®, DIOVAN HCT®, ATACAND HCT®), etc.);potassium sparing diuretics such as amiloride HCl, spironolactone,epleranone, triamterene, each with or without HCTZ; carbonic anhydraseinhibitors, such as acetazolamide; neutral endopeptidase inhibitors(e.g., thiorphan and phosphoramidon); aldosterone antagonists;aldosterone synthase inhibitors; renin inhibitors; pepstatin derivativesand fluoro- and chloro-derivatives of statone-containing peptides;enalkrein; aliskiren(2(S),4(S),5(S),7(S)—N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)-phenyl]-octanamidhemifumarate)); endothelin receptor antagonists; vasodilators (e.g.nitroprusside); calcium channel blockers (e.g., amlodipine, nifedipine,verapamil, diltiazem, felodipine, gallopamil, niludipine, nimodipine,nicardipine, bepridil, nisoldipine); potassium channel activators (e.g.,nicorandil, pinacidil, cromakalim, minoxidil, aprilkalim, loprazolam);sympatholitics; beta-adrenergic blocking drugs (e.g., acebutolol,atenolol, betaxolol, bisoprolol, carvedilol, metoprolol, metoprololtartate, nadolol, propranolol, sotalol, timolol); alpha adrenergicblocking drugs (e.g., doxazocin, prazocin or alpha methyldopa); centralalpha adrenergic agonists; peripheral vasodilators (e.g. hydralazine);nitrates or nitric oxide donating compounds, e.g. isosorbidemononitrate; lipid lowering agents, e.g., HMG-CoA reductase inhibitorssuch as simvastatin and lovastatin which are marketed as ZOCOR® andMEVACOR® in lactone pro-drug form and function as inhibitors afteradministration, and pharmaceutically acceptable salts of dihydroxy openring acid HMG-CoA reductase inhibitors such as atorvastatin(particularly the calcium salt sold in LIPITOR®), rosuvastatin(particularly the calcium salt sold in CRESTOR®), pravastatin(particularly the sodium salt sold in PRAVACHOL®), and fluvastatin(particularly the sodium salt sold in LESCOL®); a cholesterol absorptioninhibitor such as ezetimibe (ZETIA®), and ezetimibe in combination withany other lipid lowering agents such as the HMG-CoA reductase inhibitorsnoted above and particularly with simvastatin (VYTORIN®) or withatorvastatin calcium; niacin in immediate-release or controlled releaseforms, and particularly niacin in combination with a DP antagonist suchas laropiprant and/or with an HMG-CoA reductase inhibitor; niacinreceptor agonists such as acipimox and acifran, as well as niacinreceptor partial agonists; metabolic altering agents including insulinsensitizing agents and related compounds for the treatment of diabetessuch as biguanides (e.g., metformin), meglitinides (e.g., repaglinide,nateglinide), sulfonylureas (e.g., chlorpropamide, glimepiride,glipizide, glyburide, tolazamide, tolbutamide), thiazolidinediones alsoreferred to as glitazones (e.g., pioglitazone, rosiglitazone), alphaglucosidase inhibitors (e.g., acarbose, miglitol), dipeptidyl peptidaseinhibitors, (e.g., sitagliptin (JANUVIA®), alogliptin, vildagliptin,saxagliptin, linagliptin, dutogliptin, gemigliptin), SGLT2 inhibitors(e.g. sotagliflozin), ergot alkaloids (e.g., bromocriptine), combinationmedications such as JANUMET® (sitagliptin with metformin), andinjectable diabetes medications such as exenatide and pramlintideacetate; phosphodiesterase-5 (PDE5) inhibitors such as sildenafil(Revatio, Viagra), tadalafil (Cialis, Adcirca) vardenafil HCl (Levitra);or with other drugs beneficial for the prevention or the treatment ofthe above-mentioned diseases including but not limited to diazoxide; andincluding the free-acid, free-base, and pharmaceutically acceptable saltforms, pro-drug forms (including but not limited to esters), and saltsof pro-drugs of the above medicinal agents where chemically possible.Trademark names of pharmaceutical drugs noted above are provided forexemplification of the marketed form of the active agent(s); suchpharmaceutical drugs could be used in a separate dosage form forconcurrent or sequential administration with a compound of the presentinvention, or the active agent(s) therein could be used in a fixed dosedrug combination including a compound of the present invention.

The compounds of the present invention may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. In addition to thetreatment of warm-blooded animals such as mice, rats, horses, cattle,sheep, dogs, cats, monkeys, etc., the compounds of the invention areeffective for use in humans. The terms “administration of” and or“administering a” compound should be understood to mean providing acompound of the invention or a prodrug of a compound of the invention tothe individual in need of treatment.

The term “composition” as used herein is intended to encompass a productcomprising specified ingredients in predetermined amounts orproportions, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts. Such term in relation to pharmaceutical composition,is intended to encompass a product comprising the active ingredient(s),and the inert ingredient(s) that make up the carrier, as well as anyproduct which results, directly or indirectly, from combination,complexation or aggregation of any two or more of the ingredients, orfrom dissociation of one or more of the ingredients, or from other typesof reactions or interactions of one or more of the ingredients. Ingeneral, pharmaceutical compositions are prepared by uniformly andintimately bringing the active ingredient into association with a liquidcarrier or a finely divided solid carrier or both, and then, ifnecessary, shaping the product into the desired formulation. In thepharmaceutical composition the active object compound is included in anamount sufficient to produce the desired effect upon the process orcondition of diseases. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by mixing acompound of the present invention and a pharmaceutically acceptablecarrier.

Pharmaceutical compositions intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore agents selected from sweetening agents, flavoring agents, coloringagents and preserving agents in order to provide pharmaceuticallyelegant and palatable preparations. Tablets contain the activeingredient in admixture with non-toxic pharmaceutically acceptableexcipients that are suitable for the manufacture of tablets. The tabletsmay be uncoated or they may be coated by known techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. Compositions for oraluse may also be presented as hard gelatin capsules wherein the activeingredients are mixed with an inert solid diluent, for example, calciumcarbonate, calcium phosphate or kaolin, or as soft gelatin capsuleswherein the active ingredient is mixed with water or an oil medium, forexample peanut oil, liquid paraffin, or olive oil. Aqueous suspensions,oily suspensions, dispersible powders or granules, oil-in-wateremulsions, and sterile injectable aqueous or oleagenous suspension maybe prepared by standard methods known in the art. By “pharmaceuticallyacceptable” it is meant the carrier, diluent or excipient must becompatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

The subject compounds may be further useful in a method for theprevention, treatment, control, amelioration, or reduction of risk ofthe diseases, disorders and conditions noted herein. The dosage ofactive ingredient in the compositions of this invention may be varied,however, it is necessary that the amount of the active ingredient besuch that a suitable dosage form is obtained. The active ingredient maybe administered to patients (animals and human) in need of suchtreatment in dosages that will provide optimal pharmaceutical efficacy.

The selected dosage depends upon the desired therapeutic effect, on theroute of administration, and on the duration of the treatment. The dosewill vary from patient to patient depending upon the nature and severityof disease, the patient's weight, special diets then being followed by apatient, concurrent medication, and other factors which those skilled inthe art will recognize. Generally, dosage levels of between 0.001 to 10mg/kg. of body weight daily are administered to the patient, e.g.,humans and elderly humans. The dosage range will generally be about 0.5mg to 100 mg per patient per day which may be administered in single ormultiple doses. In one embodiment, the dosage range will be about 0.5 mgto 50 mg per patient per day; in another embodiment about 0.5 mg to 20mg per patient per day; and in yet another embodiment about 0.5 mg to 5mg per patient per day. Pharmaceutical compositions of the presentinvention may be provided in a solid dosage formulation such ascomprising about 0.5 mg to 100 mg active ingredient, or comprising about0.5 mg to 50 mg active ingredient. The pharmaceutical composition may beprovided in a solid dosage formulation comprising about 0.5 mg, 1 mg, 5mg, 10 mg, 25 mg, 50 mg, or 100 mg active ingredient. For oraladministration, the compositions may be provided in the form of tabletscontaining 0.5 to 100 milligrams of the active ingredient, such as 0.5,1, 5, 10, 15, 20, 25, 50, 75, and 100 milligrams of the activeingredient for the symptomatic adjustment of the dosage to the patientto be treated. The compounds may be administered on a regimen of 1 to 4times per day, such as once or twice per day.

Several methods for preparing the compounds of this invention areillustrated in the following Schemes and Examples. Starting materialsand the requisite intermediates are in some cases commerciallyavailable, or can be prepared according to literature procedures or asillustrated herein. The compounds of this invention may be prepared byemploying reactions as shown in the following schemes, in addition toother standard manipulations that are known in the literature orexemplified in the experimental procedures. Substituent numbering asshown in the schemes does not necessarily correlate to that used in theclaims and often, for clarity, a single substituent is shown attached tothe compound where multiple substituents are allowed under thedefinitions hereinabove. Reactions used to generate the compounds ofthis invention are prepared by employing reactions as shown in theschemes and examples herein, in addition to other standard manipulationssuch as ester hydrolysis, cleavage of protecting groups, etc., as may beknown in the literature or exemplified in the experimental procedures.Starting materials are made according to procedures known in the art oras illustrated herein. The following abbreviations are used herein: Me:methyl; Et: ethyl; t-Bu: tert-butyl; Ar: aryl; Ph: phenyl; Bn: benzyl;Ac: acetyl; THF: tetrahydrofuran; Boc: tert-butyloxycarbonyl; DIPEA:N,N-diisopropylethylamine; DPPA: diphenylphosphorylazide; EDC:N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide; EtOAc: ethyl acetate;HOBt: hydroxybenzotriazole hydrate; TEA: triethylamine; DMF:N,N-dimethylformamide; ACN: acetonitrile; TFA: trifluoroacetic acid;DCM: dichloromethane; DMSO: dimethyl sulfoxide; MTBE: methyl tert-butylether; DMPU: 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; DAST:Diethylaminosulfur trifluoride; TBAI: tetrabutylamonium iodide; HATU:(1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate; ttbtpy:4,4′,4″-Tri-tert-Butyl-2,2′:6′,2″-terpyridine; CAN: Ceric ammoniumnitrate; rt: room temperature; HPLC: high performance liquidchromatography; NMR: nuclear magnetic resonance; TLC: thin-layerchromatography.

The compounds of the present invention can be prepared in a variety offashions. In some cases the final product may be further modified, forexample, by manipulation of substituents. These manipulations mayinclude, but are not limited to, reduction, oxidation, alkylation,acylation, and hydrolysis reactions which are commonly known to thoseskilled in the art. In some cases the order of carrying out theforegoing reaction schemes may be varied to facilitate the reaction orto avoid unwanted reaction products. Because the schemes are anillustration, the invention should not be construed as being limited bythe chemical reactions and conditions expressed. The preparation of thevarious starting materials used herein is well within the skill of aperson versed in the art. The following examples are provided so thatthe invention might be more fully understood. These examples areillustrative only and should not be construed as limiting the inventionin any way. Absolute stereochemistry of separate stereoisomers in theexamples and intermediates are not determined unless stated otherwise inan example or explicitly in the nomenclature.

Compounds of the Formula I may be prepared by first reacting ketones oraldehydes 1 with Boc-hydrazine to afford 2 which can be treated with anacid, such as HCl to afford hydrazines 3. Reaction of hydrazines 3 witholefin 4 under basic conditions affords pyrazoles 5. Treatment of 5 withammonium hydroxide and hydrogen peroxide provides 6 which issubsequently reacted with trans racemic 7 to afford trans racemic 8. Thenitrile of 8 is then converted to pyrimidine 11 by first treatment withacidic ethanol followed by ammonia to afford 9 and annulation withdiacetal 10 to provide 11. Conversion to I occurs in three steps, firstbenzyl group removal using BCl₃ to provide 12, followed by oxidationusing an oxidant such as, for example, Dess-Martin Periodinane to afford13 and finally nitrile formation to generate I.

Alternatively, compounds of the Formula I may be prepared by firstreaction of hydrazines 3 with olefin 14 to generate pyrazole 15.Reaction of 15 with acids 16 in the presence of POCl₃ can generatecompounds I.

Cyclobutanecarboxylic acid 16a was prepared as depicted in Scheme 3.Benzyl 2-bromocyclobutanecarboxylate 18, obtained by the decarboxylativebromination of 17, was mixed with TBAI, nickel(II) iodide, ttbtpy, zinc,pyridine, and substituted bromide such as 19 in degassed DMPU to affordbenzyl 2-cyclobutanecarboxylate such as 20. The latter was thenhydrolyzed using LiOH to afford 2-cyclobutanecarboxylic acid such as16a.

Intermediate 1

2-(2-(Benzyloxy)-1-methoxyethylidene)malononitrile

Step A: 2-(Benzyloxy)acetyl chloride. Into a 5000-mL 4-neckedround-bottom flask purged and maintained with an inert atmosphere ofnitrogen, was placed 2-(benzyloxy)acetic acid (500 g, 3.01 mol),dichloromethane (2500 mL), N,N-dimethylformamide (5 mL). This wasfollowed by the addition of oxalic dichloride (458.3 g, 3.61 mol) atroom temperature. The resulting solution was stirred overnight at roomtemperature. The resulting mixture was concentrated under vacuum. Theresulting solution was diluted with 200 mL of DCM. The resulting mixturewas concentrated under vacuum. The resulting solution was diluted with200 mL of DCM. The resulting mixture was concentrated under vacuum. Thecrude material was used in next step without further purification.

Step B: 2-[2-(Benzyloxy)-1-hydroxyethylidene]propanedinitrile. Into a3000-mL 4-necked round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed tetrahydrofuran (1100 mL),propanedinitrile (195 g, 2.95 mol). This was followed by the addition ofsodium hydride (236.16 g, 5.90 mol, 60%) in several batches at 0° C.over 20 min. To this was added 2-(benzyloxy)acetyl chloride (545 g, 2.95mol) dropwise with stirring at 0° C. The resulting solution was stirredfor 2 h at 0° C. The reaction was then quenched by the addition of 500mL of water at 0° C. The resulting solution was diluted with 2000 mL ofhydrogen chloride (1 mol/L). The resulting solution was extracted with3×1000 mL of ethyl acetate and the organic layers combined. Theresulting mixture was washed with 2×1000 mL of brine. The mixture wasdried over anhydrous magnesium sulfate and concentrated under vacuum.The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:10) to afford the title compound. LCMS (ES,m/z): 215.2 [M+H]⁺.

Step C: 2-[2-(benzyloxy)-1-methoxyethylidene]propanedinitrile. Into a20-L 4-necked round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed2-[2-(benzyloxy)-1-hydroxyethylidene]propanedinitrile (457 g, 2.13 mol),dioxane (7000 mL), sodium bicarbonate (609.3 g, 7.25 mol), dimethylsulfate (376.7 g, 2.99 mol). The resulting solution was stirredovernight at 85° C. The solids were filtered out. The filtrate wasconcentrated under vacuum. The resulting solution was diluted with 2000mL of water. The resulting solution was extracted with 3×2000 mL ofethyl acetate and the organic layers combined. The resulting mixture waswashed with 2×1000 mL of brine. The mixture was dried over anhydrousmagnesium sulfate and concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:10) andafforded the title compound. LCMS (ES, m/z): 229.0 [M+H]⁺.

Intermediate 2

trans-2-(Pyrimidin-2-yl)cyclobutane-1-carboxylic acid

Step A: Diethyl 1-cyanocyclobutane-1,2-dicarboxylate. An oven driedround bottom flask was charged with diethyl 2,5-dibromohexanedioate (25g, 69.4 mmol) in ethanol (50 mL). Potassium cyanide (12.75 g, 196 mmol)was added and the contents were stirred at 90° C., for 28 h. Thereaction mixture was cooled to 0° C., brine (300 mL) was added and themixture extracted with diethyl ether (3×300 mL). The combined organicfractions were dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to yield the crude title compoundwhich was taken to next step without further purification.

Step B: Ethyl 2-cyanocyclobutanecarboxylate. An oven dried round bottomflask (500 mL) was charged with diethyl1-cyanocyclobutane-1,2-dicarboxylate (15.7 g, 69.7 mmol) in DMSO (80mL). Sodium chloride (8.15 mL, 139 mmol), water (3.14 mL, 174 mmol) wereadded and the contents were stirred at 150° C., for 4 h. The reactionmixture was cooled to 0° C., quenched with brine, extracted with diethylether (3×200 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to yield the crude title compoundwhich was taken to next step without further purification.

Step C: 2-Carbamimidoylcyclobutanecarboxylic acid hydrochloride. An ovendried round bottom flask (2000 mL) was charged with ethanol (300 mL) inchloroform (300 mL) cooled to 0° C., acetyl chloride (139 mL, 1959 mmol)was added drop wise and the contents were stirred at 0° C. for 20minutes. Ethyl 2-cyanocyclobutanecarboxylate (10.0 g, 65.3 mmol) inchloroform (50 mL) was added and the contents were stirred at roomtemperature for 12 h. The reaction mixture was concentrated underreduced pressure, the crude was dissolved in ethanol (300 mL) cooled to0° C., ammonia in methanol (410 mL, 2872 mmol) was added and thecontents were stirred at room temperature for 12 h, and concentratedunder reduced pressure to yield the crude title compound.

Step D: Methyl-2-(pyrimidin-2-yl)cyclobutanecarboxylate. An oven driedpressure tube (250 mL) was charged with crude2-carbamimidoylcyclobutanecarboxylic acid (13.0 g, 91 mmol) in1,1,3,3-tetramethoxypropane (50 mL) and the contents were stirred at160° C., for 18 h. The reaction mixture was cooled to room temperature,concentrated under reduced pressure. The crude was purified by columnchromatography on silica eluted with 20-80% ethyl acetate in petroleumether to yield the title compound. LCMS (ES, m/z): 193.4 [M+H]⁺.

Step E: 2-(Pyrimidin-2-yl)cyclobutanecarboxylic acid. An oven driedround bottom flask (100 mL) was charged with methyl2-(pyrimidin-2-yl)cyclobutanecarboxylate (4.0 g, 20.81 mmol), water(40.0 mL) and tetrahydrofuran (40.00 mL) at room temperature. Lithiumhydroxide (1.495 g, 62.4 mmol) was added and the contents were stirredat room temperature for 72 h. The reaction mixture was concentratedunder reduced pressure, and the aqueous reaction mixture was washed withdiethyl ether (2×20 mL), aqueous mass was cooled to 0° C. andneutralized with 10% potassium hydrogen sulfate, extracted with ethylacetate (3×100 mL). The combined organic layers were washed with brine(50 mL), dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure to yield the title compound. ¹H NMR (CDCl₃, 400MHz): δ 8.79 (d, J=5.20 Hz, 2H), 7.32 (t, J=4.80 Hz, 1H), 4.04-4.02 (m,1H), 3.50-3.50 (m, 1H), 2.43-2.37 (m, 4H). LCMS (ES, m/z): 179.0 [M+H]⁺.

Intermediate 3

2-(5-Methylpyrimidin-2-yl)cyclobutanecarboxylic acid

Step A: To a solution of ethanol (9.61 mL, 0.17 mol) and DCM (8.4 mL)was added AcCl (11.70 mL, 0.17 mol) at 0° C. under N₂. The reactionsolution was stirred at 0° C. for 30 min before ethyl2-cyanocyclobutanecarboxylate (1.68 g, 10.97 mmol) was added. Thereaction solution was stirred at 0° C. for 3 h, and was then graduallywarmed to 15° C.−20° C. and stirred for 6 h at this temperature beforebeing concentrated under vacuum to afford the crude product which wasused for next step directly. To a solution of the crude product in MeOH(4 mL) was added ammonia (40 mL, 0.28 mol) (7 M in MeOH) at 0° C. underN₂, and the reaction solution was stirred at room temperature for 2 hbefore being concentrated under vacuum to afford2-carbamimidoylcyclobutanecarboxylic acid, which was used directly fornext step without further purification. (ES, m/z): 143.1 [M+H]⁺.

Step B: To a solution of 2-carbamimidoylcyclobutanecarboxylic acid (1.30g, 9.14 mmol) in MeOH (2 mL) were added sodium methanolate (0.99 g,18.29 mmol) and (Z)-3-(dimethylamino)-2-methylacrylaldehyde (1.24 g,10.97 mmol) at room temperature under N₂. The reaction mixture wasdegassed with N₂ for 3 times and stirred at 80° C. for 16 h. Theresulting mixture was concentrated under vacuum. The residue wasdissolved in MeOH (5 mL) and purified by C18 column under the followingconditions: Mobile Phase A: waters with 0.5% TFA, Mobile Phase B: ACN;Flow rate: 50 mL/min; Gradient: 0% B to 60% B in 20 min; 254/210 nm. Thefractions containing desired product were combined and concentratedunder vacuum to afford 2-(5-methylpyrimidin-2-yl)cyclobutanecarboxylicacid. (ES, m/z): 193.1 [M+H]⁺.

Intermediate 4

2-(5-Bromopyrimidin-2-yl)cyclobutanecarboxylic acid

Step A: To a solution of CHCl₃ (16.30 mL) and EtOH (16.30 mL) was addedacetyl chloride (5.36 mL, 75.00 mmol) dropwise at 0° C. over 20 minutes.Ethyl 2-cyanocyclobutane-carboxylate (0.50 g, 3.26 mmol) in CHCl₃ (13mL) was then added at 0° C. dropwise to the previous solution, and thereaction solution was stirred at room temperature for 20 h. Theresulting solution was concentrated under vacuum to afford ethyl2-(ethoxy(imino)methyl)-cyclobutanecarboxylate which was used directlyfor next step without further purification. (ES, m/z): 200.1 [M+H]⁺.

Step B: To a solution of 5-bromo-1,2,3-triazine (3.98 g, 24.88 mmol) inACN (25 mL) was added ethyl2-(ethoxy(imino)methyl)cyclobutanecarboxylate (8.40 g, 42.20 mmol), andthe reaction mixture was stirred at room temperature for 5 minutesbefore heated to 80° C. and stirred for 24 h. The resulting mixture wasconcentrated under vacuum. The residue was purified by a silica gelcolumn chromatography, eluted with gradient 5%-25% EtOAc in petroleumether. The fractions containing desired product were combined andconcentrated under vacuum to afford ethyl2-(5-bromopyrimidin-2-yl)cyclobutanecarboxylate. (ES, m/z): 285.0, 287.0[M+H]⁺.

Step C: To a solution of ethyl2-(5-bromopyrimidin-2-yl)cyclobutanecarboxylate (1.00 g, 3.51 mmol) inTHF (10 mL) was added LiOH (1M in water; 5.26 mL, 5.26 mmol) at roomtemperature. The reaction mixture was stirred at room temperatureovernight before being concentrated under vacuum. The residue wasdissolved in MeOH (5 mL) and purified by Prep-HPLC with the followingconditions: column: X Bridge C18 OBD Prep Column 60 Å, 40-60 μm, 19mm×250 mm; Mobile Phase A: water with 5 mmol/L TFA, Mobile Phase B: ACN;Flow rate: 70 mL/min; Gradient: 5% B to 95% B in 8 min; 254/210 nm. Thefractions containing desired product were combined and concentratedunder vacuum to afford 2-(5-bromopyrimidin-2-yl)cyclobutanecarboxylicacid. (ES, m/z): 257.0, 259.0 [M+H]⁺.

Intermediate 5

2-(5-(Difluoromethoxy)pyrimidin-2-yl)cyclobutanecarboxylic acid

Step A: To a solution of ethyl2-(5-bromopyrimidin-2-yl)cyclobutanecarboxylate (0.20 g, 0.70 mmol) inDMF (2.5 mL) were added Cs₂CO₃ (0.46 g, 1.40 mmol), RockPhos Pd G₃(17.64 mg, 0.02 mmol) and (E)-benzaldehyde oxime (0.11 g, 0.91 mmol).The reaction mixture was degassed with N₂ for 3 times and stirred at 90°C. for 16 h. The resulting mixture was diluted with water (20 mL) andextracted with EtOAc (3×20 mL). The combined organic layers was washedwith brine (3×20 mL), dried over anhydrous Na₂SO₄ and filtered. Thefiltrate was concentrated under vacuum. The residue was purified byreverse phase (C18) column with gradient 1%-40% ACN in water with 0.05%TFA as eluent. The fractions containing desired product were combinedand concentrated under vacuum to afford ethyl2-(5-hydroxypyrimidin-2-yl)cyclobutanecarboxylate. (ES, m/z): 223.2[M+H]⁺.

Step B: To a solution of ethyl2-(5-hydroxypyrimidin-2-yl)cyclobutanecarboxylate (80 mg, 0.36 mmol) inDMF (1.2 mL) were added ethyl 2-bromo-2,2-difluoroacetate (0.22 g, 1.08mmol) and Cs₂CO₃ (0.24 g, 0.72 mmol) at room temperature. The reactionmixture was stirred at 80° C. for 48 h. The resulting mixture was cooledto room temperature and filtered. The filtrate was purified by Prep-HPLCwith the following conditions: Column: X Bridge C18 OBD Prep Column 100Å, 10 μm, 19 mm×150 mm; Mobile Phase A: water with 0.05% TFA, MobilePhase B: ACN; Flow rate: 25 mL/min; Gradient: 10% B to 35% B in 6.5 min;254/210 nm. The fractions containing desired product were combined andconcentrated under vacuum to afford ethyl2-(5-(difluoromethoxy)pyrimidin-2-yl) cyclobutanecarboxylate. (ES, m/z):273.2 [M+H]⁺.

Step C: To a solution of ethyl2-(5-(difluoromethoxy)pyrimidin-2-yl)cyclobutanecarboxylate (60.00 mg,0.22 mmol) in THF (0.5 mL) was added LiOH (1 M in water; 0.33 mL, 0.33mmol) at room temperature. The reaction mixture was stirred at roomtemperature for 16 h before being concentrated under vacuum. The residuewas dissolved in DMF and purified by Prep-HPLC with the followingconditions: column: X Bridge C18 OBD Prep Column 100 Å, 10 μm, 19 mm×150mm; Mobile Phase A: water with 0.05% TFA, Mobile Phase B: ACN; Flowrate: 25 mL/min; Gradient: 10% B to 35% B in 7 min; 254/210 nm. Thefractions containing desired product were combined and concentratedunder vacuum to afford 2-(5-(difluoromethoxy)-pyrimidin-2-yl)cyclobutanecarboxylic acid. (ES, m/z): 245.1 [M+H]⁺.

Intermediate 6

2-(5-Ethylpyrimidin-2-yl)cyclobutanecarboxylic acid

Step A: To a solution of ethyl2-(5-bromopyrimidin-2-yl)cyclobutanecarboxylate (0.10 g, 0.35 mmol) inTHF (0.50 mL) were added Pd(PPh₃)₄ (40.50 mg, 0.035 mmol) andtriethylaluminum (60.10 mg, 0.53 mmol). The reaction mixture wasdegassed with N₂ for 3 times and stirred at 70° C. for 20 h. Theresulting mixture was quenched with MeOH (2 mL), filtered and washedwith EtOAc (10 mL). The filtrate was concentrated and the residue waspurified by Prep-TLC (petroleum ether/EtOAc=2/1). The fractionscontaining desired product were combined and concentrated under vacuumto afford ethyl 2-(5-ethylpyrimidin-2-yl)cyclobutanecarboxylate. (ES,m/z): 235.1 [M+H]⁺.

Step B: To a solution of ethyl2-(5-ethylpyrimidin-2-yl)cyclobutanecarboxylate (60.00 mg, 0.26 mmol) inTHF (0.5 mL) and water (0.5 mL) was added LiOH (9.2 mg, 0.38 mmol) atroom temperature. The reaction mixture was stirred at room temperaturefor 16 h. The resulting mixture was concentrated under vacuum and theresidue was purified by Prep-HPLC with the following conditions: column:Sunfire Prep C18 OBD Column, 10 um, 19*250 mm; Mobile Phase A: waterwith 0.05% TFA, Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 12%B to 60% B in 8 min; 254/210 nm. The fractions containing desiredproduct were combined and concentrated under vacuum to afford2-(5-ethylpyrimidin-2-yl)cyclobutane-carboxylic acid. (ES, m/z): 207.1[M+H]⁺.

Intermediate 7

2-(5-Fluoropyrimidin-2-yl)cyclobutanecarboxylic acid

Step A: TBAI (86 mg, 0.23 mmol), nickel(II) iodide (29 mg, 0.09 mmol),ttbtpy (37 mg, 0.09 mmol) and zinc (0.12 g, 1.86 mmol) was added to avial. The mixture was degassed with N₂. Degassed DMPU (3 mL) was addedfollowed by pyridine (7.51 μL, 0.09 mmol). The reaction mixture wasstirred for 2 h followed by the addition of the solution of2-bromo-5-fluoropyrimidine (0.25 g, 1.39 mmol) and benzyl2-bromocyclobutanecarboxylate (0.25 g, 0.93 mmol) in DMPU (2 mL). Theresulting mixture was stirred at room temperature for 2 days beforebeing quenched with 1 M NaHSO₄, and extracted with MTBE (2×20 mL). Thecombined organic layer was washed with water (2×20 ml), brine (20 mL),dried over anhydrous MgSO₄ and filtered. The filtrate was concentratedunder vacuum. The residue was purified by silica gel columnchromatography, eluting with EtOAc/hexanes (1:20 to 1:5). The fractionscontaining desired product were combined and concentrated under vacuumto afford benzyl 2-(5-fluoropyrimidin-2-yl)cyclobutanecarboxylate (˜11:1trans:cis mixture). LCMS (m/z): 287.1 [M+H]⁺.

Step B: To a mixture of benzyl2-(5-fluoropyrimidin-2-yl)cyclobutanecarboxylate (0.25 g, 0.87 mmol) inMeOH (0.30 mL), THF (0.30 mL) and water (0.30 mL) was added LiOH (62.70mg, 2.62 mmol) at room temperature. The reaction mixture was stirred atroom temperature for 1 h. The resulting mixture was diluted with MTBEand extracted with 1 N NaOH. The pH value of the solution was adjustedto 1-2 with 6 N HCl, and extacted with MTBE (2×10 mL). The combinedorganic layer was washed with brine (3×10 mL), dried over anhydrousNa₂SO₄ and filtered. The filtrate was concentrated under vacuum. Theresidue was purified by silica gel column chromatography, eluted withgradient 0%-40% EtOAc in petroleum ether. The fractions containingdesired product were combined and concentrated under vacuum to afford2-(5-fluoropyrimidin-2-yl)cyclobutanecarboxylic acid. (ES, m/z): 197.0[M+H]⁺.

Intermediate 8

1-(2-(Trifluoromethyl)thiazol-5-yl)ethanone

Step A: To a suspension of ethyl2-(trifluoromethyl)thiazole-5-carboxylate (11.00 g, 48.80 mmol)(prepared as described by U.S. Pat. No. 5,034,404, 1991) in THF (3.00mL) and water (1.50 mL) was added NaOH (9.77 g, 244.00 mmol). Thereaction mixture was stirred at 20° C. for 4 h. The pH value of themixture was adjusted to 2-3 by 2N HCl, and the resulting mixture wasextracted with EtOAc (3×10 mL). The combined organic layer was washedwith brine (3×10 mL), dried over anhydrous Na2SO4 and filtered. Thefiltrate was concentrated under vacuum. The residue was purified by C18Phase reversal column (water:ACN=1:1). The fractions containing desiredproduct were combined and concentrated under vacuum to afford2-(trifluoromethyl)thiazole-5-carboxylic acid. (ES, m/z): 198.0 [M+H]⁺.

Step B: To the mixture of 2-(trifluoromethyl)thiazole-5-carboxylic acid(1.20 g, 6.09 mmol) in DCM (15 mL) was added N,O-dimethylhydroxylaminehydrochloride (0.59 g, 6.09 mmol). The reaction mixture was stirred atroom temperature for 5 minutes. HATU (3.47 g, 9.13 mmol) was added tothe mixture followed by the addition of Et₃N (3.39 mL 24.35 mmol) after3 minutes stirring. The reaction mixture was stirred at 20° C. for 4 hbefore being concentrated under vacuum. The residue was diluted withwater (10 mL) and extracted with DCM (3×30 mL). The combined organiclayer was washed with brine (3×10 mL), dried over anhydrous Na₂SO₄ andfiltered. The filtrate was concentrated under vacuum. The residue waspurified by silica gel column chromatography, eluted with gradient5%-25% EtOAc in petroleum ether. The fractions containing desiredproduct were combined and concentrated under vacuum to affordN-methoxy-N-methyl-2-(trifluoromethyl)thiazole-5-carboxamide. (ES, m/z):241.0 [M+H]⁺.

Step C: To a solution ofN-methoxy-N-methyl-2-(trifluoromethyl)thiazole-5-carboxamide (4.40 g,18.32 mmol) in THF (20 mL) at 0° C. under N₂ was slowly added a solutionof methylmagnesium bromide (1 M in THF) (27.50 mL, 27.50 mmol). Thereaction mixture was stirred at 0° C. for 3 h before being poured intoaq. NH₄Cl (sat.; 15 mL) and extracted with EtOAc (3×50 mL). The combinedorganic layer was washed with brine (3×30 mL), dried over anhydrousNa₂SO₄ and filtered. The filtrate was concentrated under vacuum. Theresidue was purified by silica gel column chromatography eluted withgradient 5%-25% EtOAc in petroleum ether. The fractions containingdesired product were combined and concentrated under vacuum to afford1-(2-(trifluoromethyl)thiazol-5-yl)ethanone. (ES, m/z): 196.0 [M+H]⁺.

Intermediate 9

5-Amino-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)ethyl)-1H-pyrazole-3,4-dicarbonitrile

To a solution of 2-(1-hydrazinylethyl)-5-(trifluoromethyl)pyrazine (2.20g, 5.07 mmol) in EtOH (80 mL) was added a solution of NaOH (0.41 g,10.10 mmol) in EtOH (20 mL) and ethene-1,1,2,2-tetracarbonitrile (0.71g, 5.57 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1h. To the reaction solution was added aq. NaHCO₃ (sat.; 30 mL). Theorganic solvent was removed under vacuum. The resulting mixture wasextracted with EtOAc (3×30 mL). The combined organic layer was washedwith brine (3×20 mL), dried over anhydrous Na₂SO₄ and filtered. Thefiltrate was concentrated under vacuum. The residue was purified by asilica gel column chromatography, eluted with gradient 0%-60% EtOAc inpetroleum ether. The fractions containing desired product were combinedand concentrated to afford5-amino-1-(1-(5-(trifluoromethyl)-pyrazin-2-yl)ethyl)-1H-pyrazole-3,4-dicarbonitrile.(ES, m/z): 308.1 [M+H]⁺.

TABLE 1 Exact Mass Intermediate Structure [M + H]⁺ SFC Column; Peak # 10

  enantiomer A 308.1 Chiralpak-IC; 1 11

  enantiomer B 308.1 Chiralpak IC; 2 12

  enatiomer A 289.1 Chiralpak AS-H; 1 13

  enatiomer B 289.1 Chiralpak AS-H; 2 14

  enantiomer A 246.1 Phenomenex Lux Cellulose-4; 1 15

  enantiomer B 246.1 Phenomenex Lux Cellulose-4; 2 16

  enantiomer A 279.1 Chiralpak AD-H; 1 17

  enantiomer B 279.1 Chiralpak AD-H; 2 18

257.1 No separation 19

242.1 No separation 20

313.0 No separation

The following compounds were prepared according to the general procedureprovided in the examples and procedures herein using known or preparedstarting materials, as described in the reaction schemes and examplesherein, such as described for Intermediate 9. The requisite startingmaterials are either prepared as described herein, commerciallyavailable, or may be prepared from commercially available reagents usingconventional reactions well known in the art without undueexperimentation.

Intermediate 21

5-Amino-1-(1-(2-cyclopropylpyrimidin-5-yl)ethyl)-1H-pyrazole-3,4-dicarbonitrile

Step A: To a solution of 1-(2-chloropyrimidin-5-yl)ethanone (5.00 g,31.9 mmol), tert-butyl hydrazinecarboxylate (4.22 g, 31.9 mmol) in EtOH(2 mL) was added AcOH (0.64 mL, 11.18 mmol) at room temperature. Thereaction solution was stirred for 1 h. The reaction was concentratedunder vacuum to afford (Z)-tert-butyl2-(1-(2-chloropyrimidin-5-yl)ethylidene)-hydrazinecarboxylate. The crudeproduct was used for next step directly. (ES, m/z): 271.1 [M+H]⁺.

Step B: To a solution of (Z)-tert-butyl2-(1-(2-chloropyrimidin-5-yl)ethylidene)-hydrazinecarboxylate (11.50 g,42.5 mmol) in AcOH (200 mL) was added NaCNBH₄ (3.20 g, 51.0 mmol) atroom temperature. The reaction solution was stirred overnight at roomtemperature. The reaction mixture was quenched by NH₄Cl (aq.) and thenwas concentrated. The resulted mixture was extracted with ethyl acetate(3×200 mL), washed with brine (3×200 mL), dried over with anhydrousNa₂SO₄ and filtered. The filtrate was concentrated under vacuum. Theresidue was purified by silica gel column chromatography, eluted withgradient 0-50% ethyl acetate in petroleum ether. The fractionscontaining desired product were combined and concentrated to affordtert-butyl 2-(1-(2-chloropyrimidin-5-yl)ethyl)hydrazinecarboxylate. (ES,m/z): 273.1 [M+H]⁺.

Step C: To a solution of tert-butyl2-(1-(2-chloropyrimidin-5-yl)ethyl)hydrazine-carboxylate (0.40 g, 1.47mmol) in 1,4-dioxane (4 mL) and water (2.00 mL) were addedcyclopropylboronic acid (0.38 g, 4.40 mmol), triphenylphosphine (77 mg,0.29 mmol) and Pd(OAc)₂ (32.9 mg, 0.15 mmol) at room temperature. Thereaction mixture was degassed with N₂ for 3 times and stirred for 16 hat 120° C. The reaction mixture was diluted with water (30 mL) andextracted with ethyl acetate (3×30 mL). The combined organic layer waswashed with brine (3×30 mL), dried over anhydrous Na₂SO₄ and filtered.The filtrate was concentrated under vacuum. The residue was purified bysilica gel column chromatography, eluted with gradient 0-50% ethylacetate in petroleum ether. The fractions containing desired productwere combined and concentrated to afford tert-butyl2-(1-(2-cyclopropylpyrimidin-5-yl)ethyl)hydrazinecarboxylate. (ES, m/z):279.2 [M+H]⁺.

Step D: To a solution of tert-butyl2-(1-(2-cyclopropylpyrimidin-5-yl)ethyl)hydrazinecarboxylate (0.50 g,1.80 mmol) in 1,4-dioxane (8 mL) was added 4 N HCl (13.92 mL, 55.7 mmol)in 1,4-dioxane at room temperature. The resulting solution was stirredfor 2 h at room temperature. The reaction mixture was concentrated undervacuum to afford 2-cyclopropyl-5-(1-hydrazinylethyl)pyrimidinedihydrochloride, which was used next step without purification. (ES,m/z): 179.1 [M+H]⁺.

Step E: To a solution of the2-cyclopropyl-5-(1-hydrazinylethyl)pyrimidine (0.15 g, 0.60 mmol) inEtOH (6 mL) were added a solution of NaOH (47.8 mg, 1.19 mmol) (in EtOH,2 mL) and ethene-1,1,2,2-tetracarbonitrile (77 mg, 0.60 mmol) at 0° C.The reaction mixture was stirred at 0° C. for 1 h. The resulting mixturewas extracted with ethyl acetate (3×50 mL). The combined organic layerwas washed with brine (3×50 mL), dried over anhydrous Na₂SO₄ andfiltered. The filtrate was concentrated under vacuum. The residue waspurified by a silica gel column chromatography, eluted with gradient0%-70% ethyl acetate in petroleum ether. The fractions containingdesired product were combined and concentrated to afford5-amino-1-(1-(2-cyclopropylpyrimidin-5-yl)ethyl)-1H-pyrazole-3,4-dicarbonitrile.(ES, m/z): 280.1 [M+H]⁺.

Intermediate 22

3-((Benzyloxy)methyl)-6-(2-(5-methoxypyrimidin-2-yl)cyclobutyl)-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one

Step A: To a solution of 1,1,3,3-tetraethoxypropan-2-ol (0.20 g, 0.85mmol) in THF (5 mL) were added NaH (0.051 g, 1.27 mmol) and MeI (0.079mL, 1.27 mmol). The reaction mixture was stirred at room temperature for16 h before being concentrated under vacuum. The residue was dilutedwith water (10 mL) and extracted with EtOAc (3×15 mL). The combinedorganic layer was washed with brine (3×10 mL), dried over anhydrousNa₂SO₄ and filtered. The filtrate was concentrated under vacuum toafford 1,1,3,3-tetraethoxy-2-methoxypropane, which was used directly tonext step without further purification.

Step B: To2-(3-((benzyloxy)methyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)cyclobutanecarboximidamide(0.050 g, 0.095 mmol) was added 1,1,3,3-tetraethoxy-2-methoxypropane(0.24 g, 0.95 mmol). The reaction mixture was stirred at 170° C. for 5h. The resulting mixture was purified by prep. TLC (EtOAc/Petrolether=1/1) to afford3-((benzyloxy)methyl)-6-(2-(5-methoxypyrimidin-2-yl)cyclobutyl)-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one.(ES, m/z): 592.2 [M+H]⁺.

Intermediate 23

3-((Benzyloxy)methyl)-6-(2-(5-chloropyrimidin-2-yl)cyclobutyl)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one

To a solution of2-(3-((benzyloxy)methyl)-4-oxo-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)cyclobutanecarboximidamide(0.50 g, 0.95 mmol) and 2-chloromalonaldehyde (0.20 g, 1.90 mmol) inAcOH (5 mL) was added sodium acetate (0.23 g, 2.85 mmol) at roomtemperature. Then the reaction mixture was stirred at 100° C. overnight.After cooling to room temperature, it was concentrated and quenched withsat. NaHCO₃ (aq.; 100 mL). The resulting mixture was extracted withEtOAc (3×100 mL). The combined organic layers were washed with brine(3×100 mL), dried over anhydrous Na₂SO₄, and filtered. The residue waspurified by silica gel column chromatography, eluted with gradient0%-60% EtOAc in petroleum ether. The fractions containing desiredproduct were combined and concentrated to afford3-((benzyloxy)methyl)-6-(2-(5-chloropyrimidin-2-yl)cyclobutyl)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one.(ES, m/z): 596.2 [M+H]⁺.

Intermediate 24

3-((Benzyloxy)methyl)-6-(2-(5-(difluoromethyl)pyrimidin-2-yl)cyclobutyl)-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one

Step A: To a solution of2-(3-((benzyloxy)methyl)-4-oxo-1-((S)-1-(6-(trifluoro-methyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)cyclobutane-carboximidamide(0.10 g, 0.19 mmol) in MeOH (2 mL) were added sodium methanolate (0.41g, 0.76 mmol) and[3-(dimethylamino)-2-[(dimethyliminiumyl)methyl]prop-2-en-1-ylidene]dimethyl-azaniumdiperclorate salt (0.73 g, 0.19 mmol) (prepared by Journal ofHeterocyclic Chemistry, 28 (5), 1281-5; 1991) at room temperature underargon atmosphere. The reaction mixture was stirred at 80° C. for 16 hbefore being concentrated under vacuum. The residue was purified bysilica gel column chromatography, eluted with gradient 63% EtOAc inpetroleum ether. The fractions containing desired product were combinedand concentrated under vacuum to afford2-(2-(3-((benzyloxy)methyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)cyclobutyl)pyrimidine-5-carbaldehyde.(ES, m/z): 590.2 [M+H]⁺.

Step B: To a solution of2-(2-(3-((benzyloxy)methyl)-4-oxo-1-((S)-1-(6-(trifluoro-methyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)cyclobutyl)-pyrimidine-5-carbaldehyde(0.05 g, 0.08 mmol) in DCM (1 mL) was added Deoxo-Fluor (0.045 mL, 0.34mmol) at ice bath under N₂. The reaction solution was degassed with N₂for 3 times. The resulting solution was stirred overnight at roomtemperature under nitrogen. The resulted solution was quenched with MeOHat 0° C. and concentrated under vacuum. The residue was purified bysilica gel column chromatography, eluted with gradient 50%-100% EtOAc inpetroleum ether. The fractions containing desired product were combinedand concentrated under vacuum to afford3-((benzyloxy)methyl)-6-(2-(5-(difluoromethyl)pyrimidin-2-yl)cyclobutyl)-1-((S)-1-(6-(trifluoro-methyl)pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one.(ES, m/z): 612.2 [M+H]⁺.

Intermediate 25

4-Isopropoxy-6-((1S,2S and1R,2R)-2-(pyrimidin-2-yl)cyclobutyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile

Step A: Into a 10-L 4-necked round-bottom flask purged and maintainedwith an inert atmosphere of nitrogen, was placed[(4-methoxyphenyl)methyl]hydrazine dihydrochloride (100 g, 444.22 mmol,1 equiv), ethanol (4 L), the mixture was cooled to 0° C. This wasfollowed by the addition of a solution of sodium hydroxide (35.5 g,888.43 mmol, 2 equiv) in ethanol (1.2 L) dropwise with stirring at 0° C.Eth-1-ene-1,1,2,2-tetracarbonitrile (62.6 g, 488.64 mmol, 1.1 equiv) wasadded. The resulting solution was stirred for 1 h at 0° C. The reactionmixture was quenched with water (1.5 L) and concentrated. The resultingsolution was extracted with 3×2 L of ethyl acetate and the organiclayers combined. The combined organic layer was washed with 2 L ofbrine, dried over anhydrous sodium sulfate and concentrated. The residuewas first purified by a silica gel column with ethyl acetate/petroleumether (1:1) then further to remove regioisomeric byproduct by chiralseparation (SFC) to give5-amino-1-[(4-methoxyphenyl)-methyl]-1H-pyrazole-3,4-dicarbonitrile (SFCconditions: EnantioPak-A1-5(02)5*25 cm, 5 um A1-122579-444M31595,MeOH:CO2=40:60). The second peak was the desired compound. The sameprocess was repeated 3 times.

Step B: Into a 250-mL sealed tube purged and maintained with an inertatmosphere of nitrogen, was placed5-amino-1-[(4-methoxyphenyl)methyl]-1H-pyrazole-3,4-dicarbonitrile (13g, 51.33 mmol, 1 equiv), (1S,2S and1R,2R)-2-(pyrimidin-2-yl)cyclobutane-1-carboxylic acid (10.1 g, 0.06mmol, 1.1 equiv), dichloroethane (130 mL, 1642.09 mmol, 31.99 equiv),phosphoryl trichloride (39.4 g, 0.26 mmol, 5 equiv). The resultingsolution was stirred overnight at 80° C. in sealed tube. The resultingsolution was diluted with 500 mL of ethyl acetate and quenched into anice-cold solution of aqueous sodium hydrogen carbonate (1.3 L). Theresulting solution was extracted with 3×1.3 L of ethyl acetate. Thecombined organic layer was washed with 5 L of brine, dried overanhydrous sodium sulfate and concentrated. The same process was repeatedfor 4 times and the residue was used to the next step directly.

Step C: Into a 3-L 3-necked round-bottom flask purged and maintainedwith an inert atmosphere of nitrogen, was placed i-PrOH (38.4 g, 638.99mmol, 3.000 equiv), THF (920 mL), cooled to 0° C. This was followed bythe portionwise addition of sodium hydride (17.0 g, 425.04 mmol, 1.995equiv, 60%) at 0° C., and stirred the mixture for 0.5 h at 0° C. Asolution of 4-chloro-1-[(4-methoxyphenyl)methyl]-6-[(1S,2S and1R,2R)-2-(pyrimidin-2-yl)cyclobutyl]-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile(92 g, 213.02 mmol, 1 equiv) in THF (920 mL) was added dropwise. Theresulting solution was stirred for 1 h at 0° C. The reaction was thenquenched by the addition of water. The resulting solution was extractedwith 3×1.5 L of ethyl acetate, washed with 1×1.5 L of brine. The mixturewas dried over anhydrous sodium sulfate and concentrated. The residuewas applied onto a silica gel column with ethyl acetate/petroleum ether(1:1) to provide1-[(4-methoxyphenyl)methyl]-4-(propan-2-yloxy)-6-[(1S,2S and1R,2R)-2-(pyrimidin-2-yl)cyclobutyl]-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile.

Step D: Into a 2-L 3-necked round-bottom flask purged and maintainedwith an inert atmosphere of nitrogen, was placed1-[(4-methoxyphenyl)methyl]-4-(propan-2-yloxy)-6-[(1S,2S and1R,2R)-2-(pyrimidin-2-yl)cyclobutyl]-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile(28 g, 61.47 mmol, 1 equiv), ACN (700 mL), H₂O (160 mL), followed by anaqueous suspension of CAN (118.4 g, 215.18 mmol, 3.501 equiv) in H₂O (64mL). The resulting solution was stirred for 3 h at room temperature. Thereaction was then quenched by the addition of 620 mL of sat. NaHCO₃.Extracted with 4×1.5 L of ethyl acetate and the organic layers combined.Washed with 1×1.5 L of sat. NaCl. Dried over K₂CO₃ and concentrated. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (2:1). This resulted in4-(propan-2-yloxy)-6-[(1S,2S and1R,2R)-2-(pyrimidin-2-yl)cyclobutyl]-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile.LCMS: (ES, m/z): 336 [M+H]⁺; ¹H-NMR: (300 MHz, CDCL₃, ppm): 14.43 (1H,s), 8.75-8.74 (2H, d), 7.29-7.20 (1H, t), 5.65 (1H, m), 4.38-4.24 (2H,mm), 2.66-2.48 (4H, m), 1.52-1.49 (6H, t)

Intermediate 26

(1R)-benzyl 2-bromocyclobutanecarboxylate

(1R,2S)-2-((benzyloxy)carbonyl)cyclobutanecarboxylic acid (50 g, 213mmol), 1,3-dibromo-1,3,5-triazinane-2,4,6-trione (77 g, 267 mmol),dichloroethane (1000 ml) were charged into a 2000 ml three-necked bottleunder N2. Ag(phen)2OTf (6.59 g, 10.67 mmol) was added. The resultingmixture was stirred at 70° C. for 2h. Then the reaction mixture wasdiluted with MTBE, filter, washed with NaHCO3/Na2S2O3, brine, dried overMgSO4, concentrated under vacuum. The residue was purified by silicacolumn (ethyl acetate:petroleum ether 1:50) to give (1R)-benzyl2-bromocyclo-butane-carboxylate. LC-MS: (ESI, m/z): 291 [M+Na]⁺.

Intermediates 27 and 28

(S)-5-amino-3-((benzyloxy)methyl)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxamide(INTERMEDIATE 27) and(R)-5-amino-3-((benzyloxy)methyl)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxamide(INTERMEDIATE 28)

5-Amino-3-((benzyloxy)methyl)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxamidepreparation is described below for EXAMPLES 5-8, Steps A-D. Thismaterial was resolved using chiral preparative SFC (AS-H, 21×250 mmcolumn, 40% MeOH co-solvent) to provide peak 1 (INTERMEDIATE 27,stereochemistry determined by VCD), LCMS (ES, m/z): 420.2 [M+H]⁺ andpeak 2 (INTERMEDIATE 28, stereochemistry determined by VCD), LCMS (ES,m/z): 420.2 [M+H]⁺.

Intermediates 29 and 30

(S)-5-amino-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1H-pyrazole-3,4-dicarbonitrile(INTERMEDIATE 29) and(R)-5-amino-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1H-pyrazole-3,4-dicarbonitrile(INTERMEDIATE 30)

Step A: To a solution of 1-(6-(trifluoromethyl)pyridin-3-yl)ethan-1-one(10 g, 53 mmol), tert-butyl hydrazinecarboxylate (7.7 g, 58 mmol) inEtOH (250 mL) was added AcOH (1.1 g, 17 mmol) at room temperature. Thereaction solution was stirred at 80° C. for 2 h. The reaction wasconcentrated under vacuum to afford tert-butyl2-(1-(2-chloropyrimidin-5-yl)ethylidene)hydrazinecarboxylate and useddirectly in the next step.

Step B: To a solution of tert-butyl2-(1-(6-(trifluoromethyl)pyridin-3-yl)ethylidene)hydrazine-1-carboxylate(15 g, 50 mmol) in AcOH (70 mL) and MeCN (160 ml) was added NaCNBH₄ (6.3g, 100 mmol) at room temperature. The reaction solution was stirred at80° C. for 1 h. The reaction mixture was concentrated, Et₂O (100 ml)added and 1N KOH was added to adjusted pH=13. The aqueous phase wasextracted with Et₂O (2×100 ml) and the combined organic phase, washedwith brine (100 ml), dried over with anhydrous Na₂SO₄ and filtered. Thefiltrate was concentrated under vacuum to give crude product oftert-butyl2-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)hydrazine-1-carboxylatewhich was used without further purification in the next step.

Step C: To a solution of tert-butyl2-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)hydrazine-1-carboxylate (15g, 49 mmol) was added 4 N HCl in dioxane (75 ml, 300 mmol). The reactionwas stirred at room temperature overnight and the solvent removed undervacuum. The residue was slurried in Et₂O (75 ml) and filtered to givecrude product of 5-(1-hydrazinylethyl)-2-(trifluoromethyl)pyridine HClsalt which was used without further purification in the next step.

Step D: To a solution of5-(1-hydrazinylethyl)-2-(trifluoromethyl)pyridine HCl salt (9 g, 49mmol) in EtOH (360 mL) at 0° C. were added a solution of NaOH (2.6 g, 65mmol) (in EtOH, 108 mL) and ethene-1,1,2,2-tetracarbonitrile (6.3 g, 49mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h,saturated NaHCO₃ (135 ml) added and the EtOH removed under vacuum. Theresulting mixture was extracted with ethyl acetate (3×90 mL). Thecombined organic layer was dried over anhydrous Na₂SO₄ and filtered. Thefiltrate was concentrated under vacuum. The residue was purified by asilica gel column chromatography, eluted with gradient 25% ethyl acetatein petroleum ether to give5-Amino-1-(1-(5-(trifluoromethyl)pyrazin-2-yl)ethyl)-1H-pyrazole-3,4-dicarbonitrile.This material was resolved using chiral preparative SFC (AS-H, 21×250 mmcolumn, 20% MeOH co-solvent) to provide peak 1 (INTERMEDIATE 29,stereochemistry determined by VCD), LCMS (ES, m/z): 307.1 [M+H]⁺ andpeak 2 (INTERMEDIATE 30, stereochemistry determined by VCD), LCMS (ES,m/z): 307.1 [M+H]⁺.

Intermediate 31

2-(3-((Benzyloxy)methyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)cyclobutanecarboximidamide

2-(3-((Benzyloxy)methyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)cyclobutanecarboximidamide(INTERMEDIATE 31) was prepared from(S)-5-amino-3-((benzyloxy)methyl)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxamide(INTERMEDIATE 27) using procedures described for EXAMPLES 5-8, steps Eand F, (ES, m/z): 526.2 [M+H]⁺.

Intermediates 32 and 33

(1R,2S and 1S,2R)-2-(pyrimidin-2-yl)cyclobutane-1-carboxylic acid(INTERMEDIATE 32) and (1S,2S and1R,2R)-2-(pyrimidin-2-yl)cyclobutane-1-carboxylic acid (INTERMEDIATE 33)

2-(Pyrimidin-2-yl)cyclobutane-1-carboxylic acid was prepared asdescribed herein (see INTERMEDIATE 2). This mixture was separated bysilica gel column chromatography eluting with ethyl acetate: MeOH (10:1to 3:1) to provide peak 1 and peak 2. Peak 1 was further purified byprecipitating from acetonitrile at 10-15° C. to provide Intermediate 32.LCMS (ES, m/z): 179.1 [M+H]⁺. Peak 2 was further purified by prep HPLC[Phenomenex Luna (2) C-18, 250×50 mm; 5% to 25% MeCN in water (0.09%TFA)] to provide INTERMEDIATE 33. LCMS (ES, m/z): 179.1 [M+H]+.

Examples 1-4

1-(1-(4-Fluorophenyl)ethyl)-4-oxo-6-((1,2-trans)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile

Step A: (E)-tert-Butyl2-(1-(4-fluorophenyl)ethylidene)hydrazinecarboxylate. A round bottomflask (2 L) was charged with 1-(4-fluorophenyl)ethanone (50 g, 362 mmol)in Ethanol (1 L), followed by the addition of tert-butylhydrazinecarboxylate (52.6 g, 398 mmol) and acetic acid (7.61 g, 127mmol) and the contents were stirred at 90° C. for 4 h. After which, thereaction mixture was cooled to room temperature and concentrated underreduced pressure to get the crude which was washed with petroleum ether(2×50 mL) to afford the title compound which was used without furtherpurification. ¹H NMR (400 MHz, DMSO-d₆) δ 9.84 (s, 1H), 7.79-7.75 (m,2H), 7.24-7.19 (m, 2H), 2.19 (s, 3H), 1.48 (s, 9H). LCMS (ES, m/z): 197[M+H]⁺.

Step B: tert-Butyl 2-(1-(4-fluorophenyl)ethyl)hydrazinecarboxylate. To asolution of (E)-tert-butyl2-(1-(4-fluorophenyl)ethylidene)hydrazinecarboxylate (85 g, 337 mmol) inAcetonitrile (850 mL), was added acetic acid (77 mL, 1348 mmol) andsodium cyanoborohydride (52.9 g, 842 mmol) sequentially and the contentswere stirred at 80° C. for 2.5 h. The reaction mixture was thenconcentrated, water (400 mL) and 10% sodium hydroxide solution (150 mL)were added sequentially and reaction mixture was extracted with ethylacetate (3×200 mL). The combined organic layers were washed with brine(300 mL), dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure. The residue was purified by columnchromatography (silica gel 230-400 mesh, 5-10% Ethyl acetate/Hexane) toafford the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ 8.15 (s, 1H),7.37-7.33 (m, 2H), 7.14-7.08 (m, 2H), 4.61 (s, 1H), 4.09 (d, J=7.60 Hz,1H), 1.35 (s, 9H), 1.16 (d, J=8.80 Hz, 3H). LCMS (ES, m/z): 199 [M+H]⁺.

Step C: (1-(4-Fluorophenyl)ethyl)hydrazine dihydrochloride. A roundbottom flask (1 L) containing a solution of tert-butyl2-(1-(4-fluorophenyl)ethyl)hydrazinecarboxylate (71 g, 279 mmol) indichloromethane (200 mL), was cooled to 0° C. and a solution of HCl inDioxane (400 mL, 1600 mmol) was added and the contents were stirred atambient temperature for 18 h. The reaction mixture was concentratedunder reduced pressure to get the crude which was washed with diethylether (2×50 mL) to afford the title compound. ¹H NMR (400 MHz, DMSO-d₆)δ 8.01-7.89 (m, 3H), 7.53-7.48 (m, 2H), 7.23-7.17 (m, 2H), 4.25 (q,J=8.80 Hz, 1H), 1.40 (d, J=8.80 Hz, 3H). LCMS (ES, m/z): 155 [M+H]⁺.

Step D:5-Amino-3-((benzyloxy)methyl)-1-(1-(4-fluorophenyl)ethyl)-1H-pyrazole-4-carbonitrile.To a pre-cooled solution of (1-(4-fluorophenyl)ethyl)hydrazinedihydrochloride (10 g, 44.0 mmol) in ethanol (100 mL) at 0° C. was addedsodium methoxide (5.00 g, 92 mmol) and2-(2-(benzyloxy)-1-methoxyethylidene)malononitrile (11.06 g, 48.4 mmol)sequentially and the contents were stirred at ambient temperature for 4h. The reaction mixture was concentrated under reduced pressure, water(100 mL) was added and the mixture extracted with ethyl acetate (2×100mL). The combined organic layers were washed with brine (100 mL), driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by column chromatography (silica gel230-400 mesh, 20-25% Ethyl acetate/Hexane) to afford the title compound.¹H NMR (400 MHz, DMSO-d₆) δ 7.34-7.27 (m, 7H), 7.16 (t, J=12.00 Hz, 2H),6.72 (br s, 2H), 5.54-5.52 (m, 1H), 4.49 (s, 2H), 4.37 (s, 2H), 1.68 (d,J=8.80 Hz, 3H). LCMS (ES, m/z): 351 [M+H]⁺.

Step E:5-Amino-3-((benzyloxy)methyl)-1-(1-(4-fluorophenyl)ethyl)-1H-pyrazole-4-carboxamide.To a solution of5-amino-3-((benzyloxy)methyl)-1-(1-(4-fluorophenyl)ethyl)-1H-pyrazole-4-carbonitrile(10 g, 28.5 mmol) in DMSO (150.0 mL) cooled to 0° C. was added potassiumcarbonate (19.72 g, 143 mmol) and hydrogen peroxide (14.58 mL, 143 mmol)and the contents were stirred at ambient temperature for 10 h. Thereaction mixture was cooled to 0° C. and potassium carbonate (19.72 g,143 mmol) and hydrogen peroxide (14.58 mL, 143 mmol) were added and thecontents were stirred at ambient temperature for 10 h. This cycle wasrepeated once more and the reaction was quenched with saturated sodiumthiosulfate (100 mL) solution and extracted with ethyl acetate (2×100mL). The combined organic layers were washed with brine (100 mL), driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by column chromatography (silica gel230-400 mesh, 30-35% Ethyl acetate/Hexane) to afford the title compound.¹H NMR (400 MHz, DMSO-d₆) δ 7.39-7.26 (m, 7H), 7.15 (t, J=11.60 Hz, 2H),6.92 (br s, 2H), 6.43 (br s, 2H), 5.54-5.49 (m, 1H), 4.54 (s, 2H), 4.50(s, 2H), 1.70 (d, J=9.20 Hz, 3H). LCMS (ES, m/z): 369 [M+H]⁺.

Step F:(1,2-trans)-2-(3-((Benzyloxy)methyl)-1-(1-(4-fluorophenyl)ethyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)cyclobutanecarbonitrile.A Sealed tube (100 mL) was charged with5-amino-3-((benzyloxy)methyl)-1-(1-(4-fluorophenyl)ethyl)-1H-pyrazole-4-carboxamide(5 g, 13.57 mmol) in anhydrous ethanol (50.0 mL) and 60% dispersion ofsodium hydride (1.628 g, 40.7 mmol) was added at 0° C. and the contentswere stirred at room temperature for 1 h. Then(1,2-trans)-cyclobutane-1,2-dicarbonitrile (4.32 g, 40.7 mmol) wasadded. The mixture was stirred at 140° C. for 18 h, cooled to ambienttemperature concentrated under reduced pressure, quenched with ice waterand extracted with dichloromethane (2×100 ml). The combined organiclayers were washed with brine (100 mL), dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by column chromatography (silica gel 230-400 mesh, 25-30%Ethyl acetate/Hexane) to afford the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ 12.21 (s, 1H), 7.45 (q, J=6.40 Hz, 2H), 7.35-7.26 (m, 5H),7.19-7.13 (m, 2H), 6.11-6.06 (m, 1H), 4.84 (s, 2H), 4.56 (s, 2H),3.87-3.80 (m, 2H), 2.33-2.26 (m, 4H), 1.89 (d, J=7.20 Hz, 3H). LCMS (ES,m/z): 458 [M+H]⁺.

Step G:(1,2-trans)-2-(3-((Benzyloxy)methyl)-1-(1-(4-fluorophenyl)ethyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)cyclobutanecarboximidamide.To a mixture of dry ethanol (30 mL) and chloroform (30 mL) cooled at 0°C., was added acetyl chloride (14.51 mL, 203 mmol) slowly and mixtureleft under stirring for 20 min at 0° C. Then a solution of(1,2-trans)-2-(3-((benzyloxy)methyl)-1-(1-(4-fluorophenyl)ethyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)cyclobutanecarbonitrile(3.1 g, 6.78 mmol) in dry chloroform (30 mL) was added drop wise and themixture stirred at ambient temperature for 18 h. The volatile's wereevaporated under reduced pressure, the residue re-dissolved in dryethanol (30 mL) and ammonia in methanol (48.4 mL, 6.78 mmol) was added.The mixture was stirred at ambient temperature for 24 h and the solventevaporated under reduced pressure to obtained the title compound. ¹H NMR(400 MHz, DMSO-d₆) δ 8.84 (s, 1H), 7.51-7.42 (m, 2H), 7.33-7.20 (m, 7H),7.18-7.01 (m, 3H), 6.13-6.05 (m, 1H), 4.70 (s, 2H), 4.56 (s, 2H),3.82-3.61 (m, 2H), 3.47-3.40 (m, 1H), 2.37-2.04 (m, 3H), 1.87 (d, J=9.20Hz, 3H). LCMS (ES, m/z): 475 [M+H]⁺.

Step H:3-((Benzyloxy)methyl)-1-(1-(4-fluorophenyl)ethyl)-6-((1,2-trans)-2-(pyrimidin-2-yl)cyclobutyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one.A sealed tube (50 mL) was charged with(1,2-trans)-2-(3-((benzyloxy)methyl)-1-(1-(4-fluorophenyl)ethyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyrimidin-6-yl)cyclobutanecarboximidamide(3.3 g, 6.95 mmol) and 1,1,3,3-tetramethoxypropane (14.0 mL, 6.95 mmol).The reaction mixture was stirred at 175° C. for 16 h, cooled to ambienttemperature and the solvent concentrated under reduced pressure. Theresidue was treated with dichloromethane (50 mL) and the resultingmixture stirred for 10 min. The mixture was filtered and the resultingsolution was concentrated under reduced pressure and purified by columnchromatography (silica gel 230-400 mesh, 60-80% Ethyl acetate/Hexane) toafford the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ 12.07 (s, 1H),8.81-8.78 (m, 2H), 7.44-7.40 (m, 3H), 7.40-7.26 (m, 5H), 7.17-7.08 (m,2H), 6.06-6.03 (m, 1H), 4.70 (s, 2H), 4.56 (s, 2H), 4.27-4.22 (m, 1H),3.88-3.86 (m, 1H), 2.32-2.26 (m, 4H), 1.88 (d, J=8.00 Hz, 3H). LCMS (ES,m/z): 511 [M+H]⁺.

Step I:1-(1-(4-Fluorophenyl)ethyl)-3-(hydroxymethyl)-6-((1,2-trans)-2-(pyrimidin-2-yl)cyclobutyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one.A round bottom flask (100 mL) containing a solution of3-((benzyloxy)methyl)-1-(1-(4-fluorophenyl)ethyl)-6-((1,2-trans)-2-(pyrimidin-2-yl)cyclobutyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one(1.1 g, 2.154 mmol) in dichloromethane (20 mL) was cooled to −78° C. andboron trichloride (8.62 mL, 8.62 mmol) was added and the contents werestirred at 0° C. for 30 mins. The reaction mixture was cooled to −78° C.and methanol (15.0 mL) added. The reaction was warmed to 0° C. andneutralized to pH 7 with ammonium hydroxide, diluted withdichloromethane, the layers separated and the organic layer dried oversodium sulfate, filtered and evaporated under reduced pressure to givethe title compound. ¹H NMR (400 MHz, DMSO-d₆) δ 8.81-8.78 (m, 2H),7.45-7.34 (m, 3H), 7.17-7.10 (m, 2H), 6.04-6.01 (m, 1H), 5.15 (br s,1H), 4.64 (d, J=4.80 Hz, 2H), 4.26-4.23 (m, 1H), 3.89-3.86 (m, 1H),2.33-2.31 (m, 4H), 1.81 (d, J=8.00 Hz, 3H). LCMS (ES, m/z): 421 [M+H]⁺.

Step J:1-(1-(4-Fluorophenyl)ethyl)-4-oxo-6-((1,2-trans)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbaldehyde.To a solution of1-(1-(4-fluorophenyl)ethyl)-3-(hydroxymethyl)-6-((1,2-trans)-2-(pyrimidin-2-yl)cyclobutyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one(1 g, 2.378 mmol) in dichloromethane (20 mL) was added Dess-Martinperiodinane (1.211 g, 2.85 mmol) at ambient temperature and the contentswere stirred for 30 mins. The reaction mixture was diluted withdichloromethane and quenched with saturated aqueous sodium bicarbonateand sodium thiosulfate solutions. The resulting mixture was stirred foran additional 30 mins. The organic layer was separated and dried oversodium sulfate, filtered and evaporated to give the title compound. ¹HNMR (400 MHz, DMSO-d₆) δ 10.15 (s, 1H), 8.80-8.78 (m, 2H), 7.46-7.34 (m,3H), 7.17-7.11 (m, 2H), 6.04-6.01 (m, 1H), 4.33-4.18 (m, 1H), 3.95-3.70(m, 1H), 2.34-2.30 (m, 4H), 1.93 (d, J=8.00 Hz, 3H). LCMS (ES, m/z): 419[M+H]⁺.

Step K:1-(1-(4-Fluorophenyl)ethyl)-4-oxo-6-((1,2-trans)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile.A round bottom flask (100 mL) containing1-(1-(4-fluorophenyl)ethyl)-4-oxo-6-((1,2-trans)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbaldehyde(1 g, 2.390 mmol) in acetonitrile (20.0 mL) was treated withhydroxylamine hydrochloride (0.249 g, 3.58 mmol) and DIPEA (1.252 mL,7.17 mmol). A 50% solution of propylphosphonic anhydride (3.80 g, 5.97mmol) was added drop wise to the mixture and the resulting solution washeated at 80° C. for 16 h. The reaction mixture was cooled, evaporatedin vacuo and quenched with saturated aqueous sodium bicarbonatesolution, extracted with dichloromethane (2×25 mL), dried over anhydroussodium sulfate, filtered and evaporated in vacuo. The residue waspurified by column chromatography (silica gel 230-400 mesh, 80-100%Ethyl acetate/Hexane) to obtain the title compound as a mixture of fourisomers. The isomers were separated by chiral SFC HPLC purification (20mM ammonia in methanol, column: Lux C3, Flow: 3 mL) to yield the firsteluting isomer, peak 1 as Example 1: ¹H NMR (400 MHz, DMSO-d₆) δ 12.55(s, 1H), 8.80 (d, J=4.80 Hz, 2H), 7.46 (q, J=5.60 Hz, 3H), 7.17 (t,J=8.80 Hz, 2H), 6.16-6.14 (m, 1H), 4.25-4.23 (m, 1H), 3.93-3.91 (m, 1H),2.33-2.28 (m, 4H), 1.89 (d, J=6.80 Hz, 3H), LCMS (ES, m/z): 416 [M+H]⁺,Chiral Purity: t_(R): 3.06 (100% Pure); the second eluting isomer, peak2 as Example 2: ¹H NMR (400 MHz, DMSO-d₆) δ 12.46 (s, 1H), 8.79 (d,J=4.80 Hz, 2H), 7.45-7.38 (m, 3H), 7.14-7.09 (m, 2H), 6.17-6.15 (m, 1H),4.28-4.26 (m, 1H), 3.94-3.89 (m, 1H), 2.33-2.31 (m, 4H), 1.89 (d, J=6.80Hz, 3H). LCMS (ES, m/z): 416 [M+H]⁺, Chiral Purity: t_(R): 3.52 (99.12%Pure); the third eluting isomer, peak 3 as Example 3: ¹H NMR (400 MHz,DMSO-d₆) δ 12.58 (s, 1H), 8.83-8.78 (m, 2H), 7.45-7.38 (m, 3H),7.13-7.09 (m, 2H), 6.17 (q, J=7.20 Hz, 1H), 4.28-4.26 (m, 1H), 3.92-3.90(m, 1H), 2.33-2.31 (m, 4H), 1.89 (d, J=7.20 Hz, 3H), LCMS (ES, m/z): 416[M+H]⁺, Chiral Purity: t_(R): 4.83 (97.57% Pure); the fourth elutingisomer, peak 4 as Example 4: ¹H NMR (400 MHz, DMSO-d₆) δ 12.57 (s, 1H),8.80 (d, J=4.80 Hz, 2H), 7.48-7.45 (m, 2H), 7.40 (t, J=4.80 Hz, 1H),7.20-7.16 (m, 2H), 6.16-6.14 (m, 1H), 4.25-4.23 (m, 1H), 3.93-3.91 (m,1H), 2.33-2.28 (m, 4H), 1.90 (d, J=7.20 Hz, 2H), LCMS (ES, m/z): 416[M+H]⁺, Chiral Purity: t_(R): 6.39 (97.82% Pure).

Examples 5-8

4-Oxo-6-((1,2-trans)-2-(pyrimidin-2-yl)cyclobutyl)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile

Step A: tert-Butyl2-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)hydrazinecarboxylate. Aceticacid (1.589 ml, 27.8 mmol) was added to a stirred mixture of tert-butylcarbazate (11.53 g, 87 mmol) and1-(6-(trifluoromethyl)pyridine-3-yl)ethanone (15 g, 79 mmol) in ethanol(375 ml) at ambient temperature and the mixture was stirred at 80° C.for 2 h. The solvent was removed under reduced pressure and acetonitrile(375 ml) and acetic acid (18.16 ml, 317 mmol) were added at ambienttemperature followed by sodium cyanoborohydride (9.97 g, 159 mmol). Thereaction was heated at 80° C. and after 48 hours at the solvent wasremoved under vacuum. The crude residue was dissolved in Et₂O/H₂O(150:50 ml) and pH brought to 13 by carefully adding solid KOH. Theorganic layer was separated, washed with brine (1×100 mL) dried overNa₂SO₄ and concentrated under reduced pressure to afford the titlecompound. LCMS (ES, m/z): 305 [M+H]⁺.

Step B: 5-(1-Hydrazinylethyl)-2-(trifluoromethyl)pyridinedihydrochloride. Tert-butyl2-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)hydrazine carboxylate (30 g,63.9 mmol) was dissolved in dioxane (150 ml) and hydrogen chloride (192ml, 766 mmol) was added. After 48 h a white precipitate formed and themixture was concentrated under reduced pressure to afford the titlecompound. LCMS (ES, m/z): 205 [M+H]⁺.

Step C:5-Amino-3-((benzyloxy)methyl)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carbonitrile.To a stirred, 0° C. solution of5-(1-hydrazinylethyl)-2-(trifluoromethyl)pyridine dihydrochloride (20 g,71.9 mmol) and 2-(2-(benzyloxy)-1-methoxyethylidene)malononitrile (19.7g, 86 mmol) in methanol (25 ml) was added sodium methoxide solution(0.5M, 302 ml, 151 mmol). The ice bath was removed and the solution wasallowed to stir at ambient temperature for 30 minutes. The solvent wasremoved under vacuum and the crude reaction mixture was diluted with 150mL water and 500 mL ethyl acetate. The organic layer was separated andthe aqueous phase was extracted with ethyl acetate (1×150 mL). Thecombined organic layers were dried over Na₂SO₄ and concentrated undervacuum. The crude was purified by silica gel chromatography (10-40%EtOAc in hexanes) to afford the title compound. LCMS (ES, m/z): 402.2[M+H]⁺.

Step D:5-Amino-3-((benzyloxy)methyl)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxamide.To5-amino-3-((benzyloxy)methyl)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carbonitrile(25.4 g, 63.3 mmol) in EtOH (90 ml) was added 30% aqueous hydrogenperoxide (32.6 ml, 316 mmol) solution followed by addition of ammoniumhydroxide (85 ml, 633 mmol) at 0° C. The ice bath was removed and thesolution was stirred at ambient temperature for 48 h. The reactionmixture was cooled to 0° C., slowly quenched with enough (˜3 eq.)saturated aqueous sodium thiosulfate solution to quench the peroxide Thesolvent was removed under vacuum and to the crude residue was added 200mL water, and extracted with ethyl acetate (2×250 mL). The combinedorganic layers were dried over Na₂SO₄, filtered and evaporated undervacuum to afford the title compound. LCMS (ES, m/z): 420.4 [M+H]⁺.

Step E:(1,2-trans)-2-(3-((Benzyloxy)methyl)-4-oxo-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)cyclobutanecarbonitrile.To a solution of5-amino-3-((benzyloxy)methyl)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxamide(22 g, 52.5 mmol) in EtOH (15 ml) was added 60% dispersion of sodiumhydride (6.29 g, 157 mmol) under N₂ at ambient temperature. The reactionmixture was stirred at ambient temperature for 1 h and(1,2-trans)-cyclobutane-1,2-dicarbonitrile (16.70 g, 157 mmol) wasadded. The mixture was separated into 4 batches and microwaved at 150°C. for 30 minutes each. The reactions were combined, the solvent wasremoved under vacuum and the residue was diluted with 250 mL water andextracted with EtOAc (2×250 mL). The combined EtOAc layers were driedover Na₂SO₄, concentrated under vacuum and the residue purified bysilica gel chromatography (30-50% EtOAc in hexanes) to yield the titlecompound. LCMS (ES, m/z): 509.4 [M+H]⁺.

Step F:(1,2-trans)-2-(3-((Benzyloxy)methyl)-4-oxo-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)cyclobutanecarboximidamide.A mixture of CHCl₃ (44.2 ml) and ethanol (44.2 ml) were cooled to 0° C.Acetyl chloride (14.47 ml, 204 mmol) was added drop wise to the solventmixture and stirred at 0° C. for 20 minutes.(1,2-trans)-2-(3-((Benzyloxy)methyl)-4-oxo-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)cyclobutanecarbonitrile(5 g, 8.85 mmol) in 35 mL CHCl₃ was added at 0° C. drop wise to thereaction mixture. After 48 hrs at ambient temperature the solventremoved under vacuum and the residue was dissolved in 25 mL EtOH and 25mL 7 M solution of ammonia in MeOH was added. After 48 h the solvent wasremoved under reduced pressure to afford the title compound. LCMS (ES,m/z): 526.2 [M+H]⁺.

Step G:3-((Benzyloxy)methyl)-6-((1,2-trans)-2-(pyrimidin-2-yl)cyclobutyl)-1-(1-(6(trifluoromethyl)pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one.To(1,2-trans)-2-(3-((benzyloxy)methyl)-4-oxo-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)cyclobutanecarboximidamide(2.5 g, 1.665 mmol) in 1,1,3,3-tetramethoxypropane (10 ml, 60.7 mmol)was microwaved at 150° C. for 0.5 h as 3 separate batches. The solventwas removed under reduced pressure and the residue purified by silicagel chromatography (30-60% EtOAc in hexanes) to yield the titlecompound. LCMS (ES, m/z): 562.1 [M+H]⁺.

Step H:3-(Hydroxymethyl)-6-((1,2-trans)-2-(pyrimidin-2-yl)cyclobutyl)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one.To3-((benzyloxy)methyl)-6-((1,2-trans-rac)-2-(pyrimidin-2-yl)cyclobutyl)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one(3.7 g, 6.59 mmol) in DCM (65.9 ml) at −78° C. was added trichloroborane(26.4 ml, 26.4 mmol). The solution was warmed to 0° C. and stirred at 0°C. for 15 minutes. The reaction was cooled to −78° C. and 2 mL MeOH wasadded, followed by warming to 0° C. and neutralizing to pH 7 with aqNH₄OH solution, filtered, dried over Na₂SO₄ and the solvent was removedunder vacuum to afford the title compound. LCMS (ES, m/z): 472.2 [M+H]⁺.

Step I:4-Oxo-6-((1,2-trans)-2-(pyrimidin-2-yl)cyclobutyl)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbaldehyde.To3-(hydroxymethyl)-6-((1,2-trans)-2-(pyrimidin-2-yl)cyclobutyl)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one(3.8 g, 6.45 mmol) in DCM (215 ml) at ambient temperature was addedDess-Martin periodinane (2.74 g, 6.45 mmol). After 10 minutes thereaction was diluted with 25 mL DCM and quenched with 5 mL aq sat NaHCO₃and 5 mL aq sat Na₂S₂O₃ solutions and the mixture stirred at ambienttemperature for 30 minutes. The two layers were separated and theaqueous layer was extracted with 2×25 mL DCM. The combined DCM fractionswere dried over Na₂SO₄ and concentrated in vacuuo. The residue waspurified by silica gel chromatography (2-5% MeOH: DCM) to yield thetitle compound. LCMS (ES, m/z): 470.4 [M+H]⁺

Step J:4-Oxo-6-((1,2-trans)-2-(pyrimidin-2-yl)cyclobutyl)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile.To4-oxo-6-((1,2-trans)-2-(pyrimidin-2-yl)cyclobutyl)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbaldehyde(2.7 g, 5.75 mmol) in acetonitrile (57.5 ml) at ambient temperatureunder N₂ was added hydroxylamine hydrochloride (0.600 g, 8.63 mmol)followed by drop wise addition of N-ethyl-N-isopropylpropan-2-amine(2.004 ml, 11.50 mmol). The reaction was stirred at ambient temperaturefor 5 min then 50% solution of2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (6.85ml, 11.50 mmol) was added drop wise to the reaction mixture. Thereaction mixture was heated at 80° C. for 4 hrs. The solvent was removedunder reduced pressure and the crude residue was purified by silica gelchromatography (2-5% MeOH: DCM) to yield the title compound as a mixtureof four isomers. Separation of the isomers was done by chiral SFC (OJ-H,50×250 mm column; 35% MeOH; 2.5 mL injection volume; 210 nm UVdetection; 1.6 g in 100 mL MeOH/ACN 1:1 concentration) to afford fourisomers. First eluting, peak 1 as Example 5: ¹H NMR (CDCl3) δ (ppm):2.08 (d, 3H), 2.32 (q,t, 1H), 2.54 (m, 2H), 2.73 (m, 1H), 3.77 (q, 1H),3.96 (q, 1H), 6.27 (q, 1H), 7.33 (t, 1H), 7.71 (d, 1H), 8.01 (d,d, 1H),8.84 (t, 3H), 12.33 (s, 1H). LCMS (ES, m/z): 467.2 [M+H]⁺. Secondeluting, peak 2 as Example 6: ¹H NMR (CDCl3) δ (ppm): 2.07 (d, 3H), 2.35(m, 1H), 2.53 (m, 2H), 2.66 (d,q, 1H), 3.80 (d,t, 1H), 3.93 (q, 1H),6.27 (q, 1H), 7.33 (t,d 1H), 7.74 (d,d 1H), 8.06 (d,d, 1H), 8.87 (d,d,3H), 12.38 (s, 1H). LCMS (ES, m/z): 467.2 [M+H]⁺. Third eluting, peak 3as Example 7: ¹H NMR (CDCl3) δ (ppm): 2.07 (d, 3H), 2.35 (q,d, 1H), 2.53(d,t, 1H), 2.66 (d, 1H), 3.80 (q, 1H), 3.92 (q, 1H), 6.27 (q, 1H), 7.33(s, 1H), 7.74 (d 1H), 8.06 (d,d, 1H), 8.87 (d,d, 3H), 12.38 (s, 1H).LCMS (ES, m/z): 467.2 [M+H]⁺. Fourth eluting, peak 4 as Example 8: ¹HNMR (CDCl3) δ (ppm): 2.07 (d, 3H), 2.33 (q, 1H), 2.55 (d,d, 2H), 2.72(q, 1H), 3.77 (q, 1H), 3.96 (q, 1H), 6.27 (q, 1H), 7.30 (m, 1H), 7.72(d, 1H), 8.01 (d, 1H), 8.85 (d, 3H), 12.32 (s, 1H). LCMS (ES, m/z):467.2 [M+H]⁺.

Examples 9-10

4-Oxo-6-((1,2-trans)-2-(pyrimidin-2-yl)cyclobutyl)-1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile

Step A: (E)-tert-Butyl2-((6-(trifluoromethyl)pyridin-3-yl)methylene)hydrazine-carboxylate. Around bottom flask was charged with 6-(trifluoromethyl)nicotinaldehyde(10 g, 57.1 mmol) in ethanol (200 mL), followed by the addition oftert-butyl hydrazinecarboxylate (8.30 g, 62.8 mmol) and acetic acid(1.144 ml, 19.99 mmol). The mixture was stirred at ambient temperaturefor 1 h and the reaction mixture was concentrated under reduced pressureto afford the title compound. ¹H NMR (400 MHz, DMSO-d₆): δ 11.31 (s,1H), 8.94 (s, 1H), 8.29-8.26 (m, 1H), 8.12 (s, 1H), 7.94 (d, J=11.20 Hz,1H), 1.49 (s, 9H). LCMS (ES, m/z): 290 [M+H]⁺.

Step B: tert-Butyl2-((6-(trifluoromethyl)pyridin-3-yl)methyl)hydrazine-carboxylate To asolution of (E)-tert-butyl2-((6-(trifluoromethyl)pyridin-3-yl)methylene)-hydrazinecarboxylate(15.2 g, 52.5 mmol) in methanol (150 mL) precooled at 0° C., was addedacetic acid (12.62 g, 210 mmol), followed by portion wise addition ofsodium cyanoborohydride (33.0 g, 525 mmol). The resulting reactionmixture was warmed to ambient temperature over 30 min then heated at 85°C. for 8 h. The reaction mixture was cooled to ambient temperature,water (400 mL) added and the mixture extracted with ethyl acetate (3×100mL). The combined organic layers were washed with brine (100 mL), driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by column chromatography (silica gel230-400 mesh, 30% ethyl acetate/pet ether) to afford the title compound.LCMS (ES, m/z): 292 [M+H]⁺.

Step C: 5-(Hydrazinylmethyl)-2-(trifluoromethyl)pyridinedihydrochloride. A round bottom flask containing a solution oftert-butyl2-((6-(trifluoromethyl)pyridin-3-yl)methyl)hydrazinecarboxylate (14.9 g,51.2 mmol) in dichloromethane (30 mL), was cooled to 0° C. and asolution of HCl in Dioxane (150 ml, 600 mmol) was added and the contentsstirred at ambient temperature for 18 h. The reaction mixture wasconcentrated under reduced pressure to afford the title compound whichwas used in the next step without further purification. ¹H NMR (400 MHz,DMSO-d₆): δ 8.78 (s, 1H), 8.72 (br s, 3H), 8.13 (d, J=7.92 Hz, 1H), 7.94(d, J=8.00 Hz, 1H), 4.20 (s, 2H). LCMS (ES, m/z): 192 [M+H]⁺.

Step D:5-Amino-1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazole-3,4-dicarbonitrile.To a pre-cooled solution of5-(hydrazinylmethyl)-2-(trifluoromethyl)pyridine dihydrochloride (2 g,7.57 mmol) in ethanol (20 mL) at 0° C. was added triethylamine (2.299 g,22.72 mmol) and ethene-1,1,2,2-tetracarbonitrile (0.970 g, 7.57 mmol)sequentially. The reaction mixture was stirred at ambient temperaturefor 16 h, quenched with water (100 mL) and extracted with ethyl acetate(2×100 mL). The combined organic layers were washed with brine (100 mL),dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by column chromatography(silica gel 230-400 mesh, 35% ethyl acetate/pet ether) to afford thetitle compound. ¹H NMR (400 MHz, DMSO-d₆): δ 8.69-8.61 (m, 1H),7.93-7.79 (m, 2H), 7.51 (s, 1H), 6.90 (s, 1H), 5.44 (s, 2H). LCMS (ES,m/z): 291 [M+H]⁺.

Step E:4-Oxo-6-((1,2-trans)-2-(pyrimidin-2-yl)cyclobutyl)-1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile.A pressure tube (10 mL) was charged with5-amino-1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazole-3,4-dicarbonitrile(800 mg, 2.74 mmol) in dichloroethane (16.0 mL) at room temperature,which was followed with the addition oftrans-2-(pyrimidin-2-yl)cyclobutane-1-carboxylic acid (976 mg, 5.48mmol) and phosphoryl trichloride (0.754 mL, 8.21 mmol) and the resultingcontents were stirred at 80° C. for 18 h. The reaction mixture wascooled to ambient temperature and concentrated under reduced pressure.The residue was purified by preparative HPLC (method is A: 0.1% HCOOH inH₂O B: CH₃CN, column: Atlandis dC18 (150×4.6 mm) 5 Micron, Flow: 1.2 ml)to obtain the title compound as a mixture of enantiomers. The isomerswere separated by chiral SFC HPLC purification (OJ-H, 21×250 mm column;35% MeOH, with EtOH as a co-solvent; 0.5 mL injection volume; 210 nm UVdetection; 72 in 12 mL MeOH/ACN 1:1 concentration) to yield the firsteluting isomer, peak 1 as Example 9: ¹H NMR (400 MHz, DMSO-d₆): δ 12.63(s, 1H), 8.82 (s, 1H), 8.79-8.77 (m, 2H), 8.04 (d, J=8.00 Hz, 1H), 7.88(d, J=8.00 Hz, 1H), 7.39 (t, J=4.80 Hz, 1H), 5.79 (s, 2H), 4.30-4.24 (m,1H), 3.97-3.92 (m, 1H), 2.33-2.29 (m, 4H). LCMS (ES, m/z): 453.1 [M+H]⁺.Second eluting isomer, peak 2 as Example 10: ¹H NMR (400 MHz, DMSO-d₆):δ 12.63 (s, 1H), 8.82 (s, 1H), 8.79-8.77 (m, 2H), 8.04 (d, J=8.00 Hz,1H), 7.88 (d, J=8.00 Hz, 1H), 7.39 (t, J=4.80 Hz, 1H), 5.79 (s, 2H),4.30-4.24 (m, 1H), 3.97-3.92 (m, 1H), 2.33-2.29 (m, 4H). LCMS (ES, m/z):453.1 [M+H]⁺.

TABLE 2 Exact SFC Mass Column; Example Structure Name [M + H]+ Peak # 11

1-[1-(4- cyanophenyl)ethyl]-4-oxo- 6-(2-pyrimidin-2-ylcyclobutyl)-4,5-dihydro- 1H-pyrazolo[3,4- d]pyrimidine-3-carbonitrile423.4 IF; 1 12

1-[1-(4- cyanophenyl)ethyl]-4-oxo- 6-(2-pyrimidin-2-ylcyclobutyl)-4,5-dihydro- 1H-pyrazolo[3,4- d]pyrimidine-3-carbonitrile423.4 IF; 2 13

1-[1-(4- cyanophenyl)ethyl]-4-oxo- 6-(2-pyrimidin-2-ylcyclobutyl)-4,5-dihydro- 1H-pyrazolo[3,4- d]pyrimidine-3-carbonitrile423.4 IF; 3 14

1-[1-(4- cyanophenyl)ethyl]-4-oxo- 6-(2-pyrimidin-2-ylcyclobutyl)-4,5-dihydro- 1H-pyrazolo[3,4- d]pyrimidine-3-carbonitrile423.4 IF; 4 15

1-(1-(3,4- difluorophenyl)ethyl)-4- oxo-6-(2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro- 1H-pyrazolo[3,4- d]pyrimidine-3-carbonitrile434.2 AD-H; 1 16

1-(1-(3,4- difluorophenyl)ethyl)-4- oxo-6-(2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro- 1H-pyrazolo[3,4- d]pyrimidine-3-carbonitrile434.2 AD-H; 2 17

1-(1-(3,4- difluorophenyl)ethyl)-4- oxo-6-(2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro- 1H-pyrazolo[3,4- d]pyrimidine-3-carbonitrile434.2 AD-H; 3 18

1-(1-(3,4- difluorophenyl)ethyl)-4- oxo-6-(2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro- 1H-pyrazolo[3,4- d]pyrimidine-3-carbonitrile434.2 AD-H; 4 19

4-oxo-6-[2-pyrimidin-2- ylcyclobutyl]-1-{1-[4- (trifluoromethyl)phenyl]ethyl}-4,5-dihydro-1H- pyrazolo[3,4-d]pyrimidine- 3-carbonitrile 466.3OJ-H; 1 20

4-oxo-6-[2-pyrimidin-2- ylcyclobutyl]-1-{(1S)-1-[4-(trifluoromethyl)phenyl] ethyl}-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine- 3-carbonitrile 466.3 OJ-H; 2 21

4-oxo-6-[2-pyrimidin-2- ylcyclobutyl]-1-{1-[4- (trifluoromethyl)phenyl]ethyl}-4,5-dihydro-1H- pyrazolo[3,4-d]pyrimidine- 3-carbonitrile 466.3OJ-H; 3 22

4-oxo-6-[2-pyrimidin-2- ylcyclobutyl]-1-{1-[4- (trifluoromethyl)phenyl]ethyl}-4,5-dihydro-1H- pyrazolo[3,4-d]pyrimidine- 3-carbonitrile 466.2OJ-H; 4 23

4-oxo-6-[2-pyrimidin-2- ylcyclobutyl]-1-{1-[3- (trifluoromethyl)phenyl]ethyl}-4,5-dihydro-1H- pyrazolo[3,4-d]pyrimidine- 3-carbonitrile 466.4YMC Lux C2; 1 24

4-oxo-6-[2-pyrimidin-2- ylcyclobutyl]-1-{1-[3- (trifluoromethyl)phenyl]ethyl}-4,5-dihydro-1H- pyrazolo[3,4-d]pyrimidine- 3-carbonitrile 466.4YMC Lux C2; 2 25

4-oxo-6-[2-pyrimidin-2- ylcyclobutyl]-1-{1-[3- (trifluoromethyl)phenyl]ethyl}-4,5-dihydro-1H- pyrazolo[3,4-d]pyrimidine- 3-carbonitrile 466.4YMC Lux C2; 3 26

4-oxo-6-[2-pyrimidin-2- ylcyclobutyl]-1-{1-[3- (trifluoromethyl)phenyl]ethyl}-4,5-dihydro-1H- pyrazolo[3,4-d]pyrimidine- 3-carbonitrile 466.4YMC Lux C2; 4

The following compounds were prepared according to the general procedureprovided in the examples and procedures herein using known or preparedstarting materials, as described in the reaction schemes and examplesherein. The requisite starting materials are either prepared asdescribed in the intermediates section, commercially available, or maybe prepared from commercially available reagents using conventionalreactions well known in the art without undue experimentation.

TABLE 3 Prep- Chiral Exact HPLC HPLC Mass Condition; Condition; Ex.Structure Name [M + H]⁺ Peak # Peak # 27

  Isomer A 4-oxo-6-(2-(pyrimidin-2- yl)cyclobutyl)-1-(1-(5-(trifluoromethyl)- pyrazin-2-yl)ethyl)-4,5- dihydro-1H- pyrazolo[3,4-d]pyrimidine-3- carbonitrile 468.1 Condition A Condition B; 1 28

  Isomer B 4-oxo-6-(2-(pyrimidin-2- yl)cyclobutyl)-1-(1-(5-(trifluoromethyl)- pyrazin-2-yl)ethyl)-4,5- dihydro-1H- pyrazolo[3,4-d]pyrimidine-3- carbonitrile 468.1 See above (Ex. 27) Condition B; 2 29

  Isomer C 4-oxo-6-(2-(pyrimidin-2- yl)cyclobutyl)-1-(1-(5-(trifluoromethyl)- pyrazin-2-yl)ethyl)-4,5- dihydro-1H- pyrazolo[3,4-d]pyrimidine-3- carbonitrile 468.1 See above (Ex. 27) Condition B; 3 30

  Isomer D 4-oxo-6-(2-(pyrimidin-2- yl)cyclobutyl)-1-(1-(5-(trifluoromethyl)- pyrazin-2-yl)ethyl)-4,5- dihydro-1H- pyrazolo[3,4-d]pyrimidine-3- carbonitrile 468.1 See above (Ex. 27) Condition B; 4 31

  Isomer C 6-(2-(5-methyl- pyrimidin-2- yl)cyclobutyl)-4-oxo-1-(1-(6-(trifluoromethyl)- pyridin-3-yl)ethyl)-4,5- dihydro-1H-pyrazolo[3,4- d]pyrimidine-3- carbonitrile 481.2 Condition A; Peak 2 wasfurther purified (Condition A) to give 31 — 32

  Isomer D 6-(2-(5-methyl- pyrimidin-2- yl)cyclobutyl)-4-oxo-1-(1-(6-(trifluoromethyl)- pyridin-3-yl)ethyl)-4,5- dihydro-1H-pyrazolo-[3,4-d]pyrimidine-3- carbonitrile 481.2 Condition A; 3 Condition B; 1 33

  Isomer E 6-(2-(5-methyl- pyrimidin-2- yl)cyclobutyl)-4-oxo-1-(1-(6-(trifluoromethyl)- pyridin-3-yl)ethyl)-4,5- dihydro-1H-pyrazolo-[3,4-d]pyrimidine-3- carbonitrile 481.2 Condition A; 3 Condition B; 2 34

  Isomer A 4-oxo-6-(2-(pyrimidin-2- yl)cyclobutyl)-1-(1-(2-(trifluoromethyl)- pyrimidin-5-yl)ethyl)- 4,5-dihydro-1H- pyrazolo[3,4-d]pyrimidine-3- carbonitrile 468.1 — Condition B; 1 35

  Isomer B 4-oxo-6-(2-(pyrimidin-2- yl)cyclobutyl)-1-(1-(2-(trifluoromethyl)- pyrimidin-5-yl)ethyl)- 4,5-dihydro-1H- pyrazolo[3,4-d]pyrimidine-3- carbonitrile 468.1 — Condition B; 2 36

  Isomer C 4-oxo-6-(2-(pyrimidin-2- yl)cyclobutyl)-1-(1-(2-(trifluoromethyl)- pyrimidin-5-yl)ethyl)- 4,5-dihydro-1H- pyrazolo[3,4-d]pyrimidine-3- carbonitrile 468.1 — Condition C; 1 37

  Isomer D 4-oxo-6-(2-(pyrimidin-2- yl)cyclobutyl)-1-(1-(2-(trifluoromethyl)- pyrimidin-5-yl)ethyl)- 4,5-dihydro-1H- pyrazolo[3,4-d]pyrimidine-3- carbonitrile 468.1 — Condition C; 2 38

  Isomer AA (Obtained using Intermediate 12) 1-(1-(6-(difluoromethyl)pyridin- 3-yl)ethyl)-4-oxo-6-(2- (pyrimidin-2-yl)cyclobutyl)-4,5- dihydro-1H- pyrazolo[3,4- d]pyrimidine-3-carbonitrile 449.2 Condition A; 1 Condition D; 1 39

  Isomer AB (Obtained using Intermediate 12) 1-(1-(6-(difluoro-methyl)pyridin-3- yl)ethyl)-4-oxo-6-(2- (pyrimidin-2-yl)cyclo-butyl)-4,5-dihydro-1H- pyrazolo[3,4- d]pyrimidine-3- carbonitrile 449.2Condition A; 1 Condition D; 2 40

  Isomer BA (Obtained using Intermediate 12) 1-(1-(6-(difluoro-methyl)pyridin-3- yl)ethyl)-4-oxo-6-(2- (pyrimidin-2-yl)cyclobutyl)-4,5- dihydro-1H- pyrazolo[3,4- d]pyrimidine-3-carbonitrile 449.2 Condition A; 2 Condition C; 1 41

  Isomer BB (Obtained using Intermediate 12) 1-(1-(6-(difluoro-methyl)pyridin-3- yl)ethyl)-4-oxo-6-(2- (pyrimidin-2-yl)cyclobutyl)-4,5- dihydro-1H- pyrazolo[3,4- d]pyrimidine-3-carbonitrile 449.2 Condition A; 2 Condition C; 2 42

  Isomer CA (Obtained using Intermediate 13) 1-(1-(6-(difluoro-methyl)pyridin-3- yl)ethyl)-4-oxo-6-(2- (pyrimidin-2-yl)cyclobutyl)-4,5- dihydro-1H- pyrazolo[3,4- d]pyrimidine-3-carbonitrile 449.2 Condition A; 1 Condition E; 1 43

  Isomer CB (Obtained using Intermediate 13) 1-(1-(6-(difluoro-methyl)pyridin-3- yl)ethyl)-4-oxo-6-(2- (pyrimidin-2-yl)cyclobutyl)-4,5- dihydro-1H- pyrazolo[3,4- d]pyrimidine-3-carbonitrile 449.2 Condition A; 1 Condition E; 2 44

  Isomer DA (Obtained using Intermediate 13) 1-(1-(6-(difluoro-methyl)pyridin-3- yl)ethyl)-4-oxo-6-(2- (pyrimidin-2-yl)cyclobutyl)-4,5- dihydro-1H- pyrazolo[3,4- d]pyrimidine-3-carbonitrile 449.2 Condition A; 2 Condition C; 1 45

  Isomer DB (Obtained using Intermediate 13) 1-(1-(6-(difluoro-methyl)pyridin-3- yl)ethyl)-4-oxo-6-(2- (pyrimidin-2-yl)cyclobutyl)-4,5- dihydro-1H- pyrazolo[3,4- d]pyrimidine-3-carbonitrile 449.2 Condition A; 2 Condition C; 2 46

  Isomer A 4-oxo-6-(2-(pyrimidin-2- yl)cyclobutyl)-1-(1-(tetrahydro-2H-pyran-4- yl)ethyl)-4,5-dihydro- 1H-pyrazolo[3,4-d]pyrimidine-3- carbonitrile 406.2 — Condition B; 1 47

  Isomer B 4-oxo-6-(2-(pyrimidin-2- yl)cyclobutyl)-1-(1-(tetrahydro-2H-pyran-4- yl)ethyl)-4,5-dihydro- 1H-pyrazolo[3,4-d]pyrimidine-3- carbonitrile 406.2 — Condition B; 2 48

  Isomer C 4-oxo-6-(2-(pyrimidin-2- yl)cyclobutyl)-1-(1-(tetrahydro-2H-pyran-4- yl)ethyl)-4,5-dihydro- 1H-pyrazolo[3,4-d]pyrimidine-3- carbonitrile 406.2 — Condition F; 1 49

  Isomer D 4-oxo-6-(2-(pyrimidin-2- yl)cyclobutyl)-1-(1-(tetrahydro-2H-pyran-4- yl)ethyl)-4,5-dihydro- 1H-pyrazolo[3,4-d]pyrimidine-3- carbonitrile 406.2 — Condition F; 2 50

  Isomer AA (Obtained using Intermediate 16) 1-(1-(6-cyclopropylpyridin-3- yl)ethyl)-4-oxo-6-(2- (pyrimidin-2-yl)cyclobutyl)-4,5- dihydro-1H- pyrazolo[3,4- d]pyrimidine-3-carbonitrile 439.2 Condition A; 1 Condition B; 1 51

  Isomer AB (Obtained using Intermediate 16) 1-(1-(6-cyclopropylpyridin-3- yl)ethyl)-4-oxo-6-(2- (pyrimidin-2-yl)cyclobutyl)-4,5- dihydro-1H- pyrazolo[3,4- d]pyrimidine-3-carbonitrile 439.2 Condition A; 1 Condition B; 2 52

  Isomer BA (Obtained using Intermediate 16) 1-(1-(6-cyclopropyl-pyridin-3-yl)ethyl)-4- oxo-6-(2-(pyrimidin-2- yl)cyclobutyl)-4,5-dihydro-1H- pyrazolo[3,4- d]pyrimidine-3- carbonitrile 439.2 ConditionA; 2 Condition G; 1 53

  Isomer BB (Obtained using Intermediate 16) 1-(1-(6-cyclopropyl-pyridin-3-yl)ethyl)-4- oxo-6-(2-(pyrimidin-2- yl)cyclobutyl)-4,5-dihydro-1H- pyrazolo[3,4- d]pyrimidine-3- carbonitrile 439.2 ConditionA; 2 Condition G; 2 54

  Isomer CA (Obtained using Intermediate 17) 1-(1-(6-cyclopropyl-pyridin-3-yl)ethyl)-4- oxo-6-(2-(pyrimidin-2- yl)cyclobutyl)-4,5-dihydro-1H- pyrazolo[3,4- d]pyrimidine-3- carbonitrile 439.2 ConditionA; 1 Condition G; 1 55

  Isomer CB (Obtained using Intermediate 17) 1-(1-(6-cyclopropyl-pyridin-3-yl)ethyl)-4- oxo-6-(2-(pyrimidin-2- yl)cyclobutyl)-4,5-dihydro-1H- pyrazolo[3,4- d]pyrimidine-3- carbonitrile 439.2 ConditionA; 1 Condition G; 2 56

  Isomer DA (Obtained using Intermediate 17 in Table 31-(1-(6-cyclopropyl- pyridin-3-yl)ethyl)-4- oxo-6-(2-(pyrimidin-2-yl)cyclobutyl)-4,5- dihydro-1H- pyrazolo[3,4- d]pyrimidine-3-carbonitrile 439.2 Condition A; 2 Condition B; 1 57

  Isomer DB Obtained using Intermediate 17) 1-(1-(6-cyclopropyl-pyridin-3-yl)ethyl)-4- oxo-6-(2-(pyrimidin-2- yl)cyclobutyl)-4,5-dihydro-1H- pyrazolo[3,4- d]pyrimidine-3- carbonitrile 439.2 ConditionA; 2 Condition B; 2 58

  Isomer A 6-(2-(5-bromo- pyrimidin-2- yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoro- methyl)pyridin-3- yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4- d]pyrimidine-3- carbonitrile  545.1, 547.1 — ConditionB; 1 59

  Isomer B 6-(2-(5-bromo- pyrimidin-2- yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoro- methyl)pyridin-3- yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4- d]pyrimidine-3- carbonitrile  545.1, 547.1 — ConditionB; 2 60

  Isomer A 6-(2-(5-(difluoro- methoxy)pyrimidin-2-yl)cyclobutyl)-4-oxo-1- ((S)-1-(6-(trifluoro- methyl)pyridin-3-yl)ethyl)-4,5-dihydro- 1H-pyrazolo[3,4- d]pyrimidine-3- carbonitrile533.1 — Condition B; 1 61

  Isomer B 6-(2-(5-(difluoro- methoxy)pyrimidin-2-yl)cyclobutyl)-4-oxo-1- ((S)-1-(6-(trifluoro- methyl)pyridin-3-yl)ethyl)-4,5-dihydro- 1H-pyrazolo[3,4- d]pyrimidine-3- carbonitrile533.1 — Condition B; 2 62

  Isomer A 6-(2-(5-ethylpyrimidin-2- yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoro- methyl)pyridin-3- yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4- d]pyrimidine-3- carbonitrile 495.2 — Condition H; 1 63

  Isomer B 6-(2-(5-ethylpyrimidin-2- yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoro- methyl)pyridin-3- yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4- d]pyrimidine-3- carbonitrile 495.2 — Condition H; 2 64

  Isomer AA 1-(1-(5-fluoropyridin-3- yl)ethyl)-4-oxo-6-(2- (pyrimidin-2-yl)cyclobutyl)-4,5- dihydro-1H- pyrazolo[3,4- d]pyrimidine-3-carbonitrile 417.2 — Condition I; Peak 1 was further separated byCondition B; 1 65

  Isomer AB 1-(1-(5-fluoropyridin-3- yl)ethyl)-4-oxo-6-(2- (pyrimidin-2-yl)cyclobutyl)-4,5- dihydro-1H- pyrazolo[3,4- d]pyrimidine-3-carbonitrile 417.2 — Condition I; Peak 1 was further separated byCondition B; 2 66

  Isomer B 1-(1-(5-fluoropyridin-3- yl)ethyl)-4-oxo-6-(2- (pyrimidin-2-yl)cyclobutyl)-4,5- dihydro-1H- pyrazolo[3,4- d]pyrimidine-3-carbonitrile 417.2 — Condition I; 2 67

  Isomer C 1-(1-(5-fluoropyridin-3- yl)ethyl)-4-oxo-6-(2- (pyrimidin-2-yl)cyclobutyl)-4,5- dihydro-1H- pyrazolo[3,4- d]pyrimidine-3-carbonitrile 417.2 — Condition I; 3 68

  Isomer AA 1-(1-(1-methyl-1H- pyrazol-4-yl)ethyl)-4-oxo-6-(2-(pyrimidin-2- yl)cyclobutyl)-4,5- dihydro-1H- pyrazolo[3,4-d]pyrimidine-3- carbonitrile 402.2 — Condition J; Peak 1 was furtherseparated by Condition G; 1 69

  Isomer AB 1-(1-(1-methyl-1H- pyrazol-4-yl)ethyl)-4-oxo-6-(2-(pyrimidin-2- yl)cyclobutyl)-4,5- dihydro-1H- pyrazolo[3,4-d]pyrimidine-3- carbonitrile 402.2 — Condition J; Peak 1 was furtherseparated by Condition G; 2 70

  Isomer B 1-(1-(1-methyl-1H- pyrazol-4-yl)ethyl)-4-oxo-6-(2-(pyrimidin-2- yl)cyclobutyl)-4,5- dihydro-1H- pyrazolo[3,4-d]pyrimidine-3- carbonitrile 402.2 — Condition J; 2 71

  Isomer C 1-(1-(1-methyl-1H- pyrazol-4-yl)ethyl)-4-oxo-6-(2-(pyrimidin-2- yl)cyclobutyl)-4,5- dihydro-1H- pyrazolo[3,4-d]pyrimidine-3- carbonitrile 402.2 — Condition J; 3 72

  Isomer A 1-(1-(6-cyclopropyl- pyridin-3-yl)ethyl)-6-(2-(5-fluoropyrimidin-2- yl)cyclobutyl)-4-oxo-4,5- dihydro-1H-pyrazolo[3,4- d]pyrimidine-3- carbonitrile 457.2 — Condition B; 1 73

  Isomer B 1-(1-(6-cyclopropyl- pyridin-3-yl)ethyl)-6-(2-(5-fluoropyrimidin-2- yl)cyclobutyl)-4-oxo-4,5- dihydro-1H-pyrazolo[3,4- d]pyrimidine-3- carbonitrile 457.2 — Condition B; 2 74

  Isomer C 1-(1-(6-cyclopropyl- pyridin-3-yl)ethyl)-6-(2-(5-fluoropyrimidin-2- yl)cyclobutyl)-4-oxo-4,5- dihydro-1H-pyrazolo[3,4- d]pyrimidine-3- carbonitrile 457.2 — Condition B; 1 75

  Isomer D 1-(1-(6-cyclopropyl- pyridin-3-yl)ethyl)-6-(2-(5-fluoropyrimidin-2- yl)cyclobutyl)-4-oxo-4,5- dihydro-1H-pyrazolo[3,4- d]pyrimidine-3- carbonitrile 457.2 — Condition B; 2 76

  Isomer A 4-oxo-6-(2-(pyrimidin-2- yl)cyclobutyl)-1-(1-(2-(trifluoromethyl)thiazol- 5-yl)ethyl)-4,5-dihydro- 1H-pyrazolo[3,4-d]pyrimidine-3- carbonitrile 473.1 — Condition B; 2 77

  Isomer BA 4-oxo-6-(2-(pyrimidin-2- yl)cyclobutyl)-1-(1-(2-(trifluoromethyl)thiazol- 5-yl)ethyl)-4,5-dihydro- 1H-pyrazolo[3,4-d]pyrimidine-3- carbonitrile 473.1 — Condition B; Peak 2 was furtherseparated by Condition F; 1 78

  Isomer BB 4-oxo-6-(2-(pyrimidin-2- yl)cyclobutyl)-1-(1-(2-(trifluoromethyl)thiazol- 5-yl)ethyl)-4,5-dihydro- 1H-pyrazolo[3,4-d]pyrimidine-3- carbonitrile 473.1 — Condition B; Peak 2 was furtherseparated by Condition F; 2 79

  Isomer C 4-oxo-6-(2-(pyrimidin-2- yl)cyclobutyl)-1-(1-(2-(trifluoromethyl)thiazol- 5-yl)ethyl)-4,5-dihydro- 1H-pyrazolo[3,4-d]pyrimidine-3- carbonitrile 473.1 — Condition B; 3 80

  Isomer A 1-(1-(2-cyclopropyl- pyrimidin-5-yl)ethyl)-6- ((1S,2S)-2-(5-fluoropyrimidin-2- yl)cyclobutyl)-4-oxo-4,5- dihydro-1H- pyrazolo[3,4-d]pyrimidine-3- carbonitrile 458.2 — Condition B; 1 81

  Isomer B 1-(1-(2-cyclopropyl- pyrimidin-5-yl)ethyl)-6- ((1S,2S)-2-(5-fluoropyrimidin-2- yl)cyclobutyl)-4-oxo-4,5- dihydro-1H- pyrazolo[3,4-d]pyrimidine-3- carbonitrile 458.2 — Condition B; 2

The following compounds were prepared according to the general procedureprovided in the examples and procedures herein using known or preparedstarting materials, as described in the reaction schemes and examplesherein, such as described for Examples 9-10. The reaction mixture wasconcentrated after treatment with phosphoryl trichloride. The cruderesidue was dissolved in ACN/H₂O (˜3:1 ratio) at room temperature. Thereaction solution was stirred at 50° C. overnight and concentrated undervacuum. The residue thus obtained was purified by reverse phase HPLC,and then chiral HPLC if required. The requisite starting materials areeither prepared as described in the intermediates section, commerciallyavailable, or may be prepared from commercially available reagents usingconventional reactions well known in the art without undueexperimentation. General purification condition for Prep HPLC (ConditionA): X Bridge C18 OBD Prep Column 100 Å, 10 μm, 19 mm×250 mm; MobilePhase A: water with 20 mmol/L NH₄HCO₃, Mobile Phase B: ACN; Flow rate:20 mL/min; Gradient: 20-50% B to 50-80% B. Chiral HPLC conditions:Condition B: CHIRALPAK-IC, 2×25 cm, 5 μm; Mobile Phase A:Hex:DCM=3:1 orHex:DCM=1:1 or Hex or EtOH:DCM=3:1; Mobile Phase B: EtOH: 15-50% or IPA40-50% or MeOH:IPA=1:1, 60%. Condition C: Chiralpak IA, 2×25 cm, 5 μm;Mobile Phase A: Hex:DCM=3:1 or Hex; Mobile Phase B: EtOH: 20-100%.Condition D: CHIRALPAK IE, 2×25 cm, 5 μm; Mobile Phase A: Hex, MobilePhase B: EtOH: 23%. Condition E: (R,R)-WHELK-01-Kromasil, 5×25 cm, 5 μm;Mobile Phase A: Hex, Mobile Phase B: EtOH: 30%. Condition F: CHIRAL ARTCellulose-SB, 2×25 cm, 5 μm; Mobile Phase A: Hex, Mobile Phase B: IPA:40% or EtOH 30%. Condition G: CHIRALPAK AD-H, 2×25 cm; Mobile PhaseA:Hex, Mobile Phase B: EtOH: 15-20%. Condition H: CHIRALPAK AS-H, 5×25cm, 5 μm; Mobile Phase A: Hex, Mobile Phase B: EtOH: 30% or IPA 50%.Condition I: CHIRALPAK ID-03, 2×25 cm, 5 μm; Mobile Phase A: Hex, MobilePhase B: IPA: 40%. Condition J: CHIRALPAK IG UL001, 2×25 cm, 5 μm;Mobile Phase A: Hex, Mobile Phase B: EtOH: 40-50%.

Example 82

6-(2-(5-ethynylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile

Step A: To a solution of 1-tributylstannyl-2-trimethylsilylacetylene(34.5 mg, 0.089 mmol) in DMF (500 μl), was added6-(2-(5-bromopyrimidin-2-yl)cyclobutyl)-4-oxo-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile(24.3 mg, 0.045 mmol) and PdCl2(dppf) (3.26 mg, 4.46 μmol) at roomtemperature. The reaction mixture was stirred at 100° C. for 2 h. Themixture was cooled, aqueous ammonium chloride (saturated, 10 mL) wasadded and the mixture was extracted with ethyl acetate (3×15 mL). Thecombined organic fractions were washed with aqueous ammonium chloride(saturated, 15 mL), dried (MgSO₄), filtered and the solvent wasevaporated under reduced pressure. The residue was purified bypreparative reverse phase LC (C-18) RediSep Rf 50 g HP, eluting withAcetonitrile/Water from 5 to 100%, wavelength 254 mm, to give4-oxo-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-6-(2-(5-((trimethylsilyl)ethynyl)pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile.LCMS (ES, m/z): 653.3 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) δ 11.98 (s,1H), 8.85 (d, J=1.8 Hz, 1H), 8.82 (s, 2H), 8.02 (dd, J=2.0, 8.2 Hz, 1H),7.71 (d, J=8.2 Hz, 1H), 6.23 (q, J=7.1 Hz, 1H), 3.89 (q, J=9.4 Hz, 1H),3.76 (q, J=9.7 Hz, 1H), 2.63 (p, J=10.3 Hz, 1H), 2.48 (td, J=5.7, 9.9,10.5 Hz, 2H), 2.32 (ddd, J=5.2, 10.6, 13.7 Hz, 1H), 2.04 (d, J=7.2 Hz,3H), 0.28 (s, 9H).

Step B: To a solution of4-oxo-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-6-(2-(5-((trimethylsilyl)ethynyl)pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile(16.1 mg, 0.029 mmol) in acetonitrile (500 μl), was added TBAF (60 μl,0.060 mmol) at room temperature. The reaction mixture was stirred atroom temperature for 1 h. The mixture was cooled, aqueous ammoniumchloride (saturated, 10 mL) was added and the mixture was extracted withethyl acetate (3×15 mL). The combined organic fractions were washed withaqueous ammonium chloride (saturated, 15 mL), dried (MgSO₄), filteredand the solvent was evaporated under reduced pressure. The residue waspurified by preparative LC Reverse phase (C-18) RediSep Rf 50 g HP,eluting with Acetonitrile/Water from 5 to 100% wavelength 254 mm. Thiswas further purified by preparative LC Reverse phase (C-18), elutingwith Acetonitrile/Water from 7 to 100%, to give EXAMPLE 82,6-(2-(5-ethynylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile.LCMS (ES, m/z): 491.2 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) δ 8.87 (s,2H), 8.86-8.84 (m, 1H), 8.03 (d, J=6.9 Hz, 1H), 7.71 (d, J=8.2 Hz, 1H),6.23 (q, J=7.1 Hz, 1H), 3.91 (q, J=9.4 Hz, 1H), 3.77 (q, J=9.6 Hz, 1H),3.42 (s, 1H), 2.64 (p, J=10.2 Hz, 1H), 2.49 (dt, J=4.6, 9.3 Hz, 2H),2.32 (tt, J=5.1, 10.7 Hz, 1H), 2.04 (d, J=7.2 Hz, 3H).

Examples 83-84

6-((1R,2R)-2-(5-fluoropyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile6-((1S,2S)-2-(5-fluoropyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile

In a 20 mL vial, a suspension of2-(5-fluoropyrimidin-2-yl)cyclobutanecarboxylic acid (0.961 g, 4.90mmol) and(S)-5-amino-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1H-pyrazole-3,4-dicarbonitrile(1.25 g, 4.08 mmol) in dichloroethane (17 ml) was charged with POCl₃(1.141 ml, 12.25 mmol). The vial was capped, and the reaction mixturewas heated to 60° C. over night. The reaction mixture was cooled to roomtemperature. The reaction mixture was transferred to a flask and thesolvent was removed under vacuum. Acetonitrile (12.0 mL) and water (5mL) were charged to the reaction mixture, which was then heated to 50°C. for 3 hours. The reaction mixture was cooled down to room temperatureand charged with aqueous sodium hydrogen carbonate (saturated, 30 mL).It was extracted with ethyl acetate (3×30 mL). The combined organicfractions were dried (Na₂SO₄), filtered and the solvent was evaporatedunder reduced pressure. The residue was purified by columnchromatography on silica gel RediSep Gold 120 g silica, eluting withMeOH/DCM 0-8% to give6-(2-(5-fluoropyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile.The title compounds were obtained by chiral preparative SFC (ChiralpakOJ-H, 21×250 mm, 20% MeOH). The faster-eluting isomer of the titlecompound (EXAMPLE 83). LCMS (ES, m/z): 485.4 [M+H]⁺. ¹H NMR (500 MHz,Chloroform-d) δ 11.67 (s, 1H), 8.81 (s, 1H), 8.70 (s, 2H), 7.99 (d,J=8.5 Hz, 1H), 7.69 (d, J=8.1 Hz, 1H), 6.24 (q, J=7.1 Hz, 1H), 3.91 (q,J=9.4 Hz, 1H), 3.72 (q, J=9.7 Hz, 1H), 2.71 (dt, J=20.8, 11.0 Hz, 1H),2.49 (dq, J=21.2, 10.6, 9.7 Hz, 2H), 2.30 (q, J=8.9, 8.3 Hz, 1H), 2.06(d, J=7.2 Hz, 3H). The slower-eluting isomer of the title compound(EXAMPLE 84). LCMS (ES, m/z): 485.4 [M+H]⁺. ¹H NMR (500 MHz,Chloroform-d) δ 11.74 (s, 1H), 8.86 (s, 1H), 8.69 (s, 2H), 8.04 (d,J=7.9 Hz, 1H), 7.72 (d, J=8.2 Hz, 1H), 6.23 (q, J=7.2 Hz, 1H), 3.87 (q,J=9.3 Hz, 1H), 3.75 (q, J=9.4 Hz, 1H), 2.64 (dt, J=20.4, 10.7 Hz, 1H),2.56-2.40 (m, 2H), 2.37-2.26 (m, 1H), 2.04 (d, J=7.2 Hz, 3H).

Example 85

6-(2-(5-fluoropyrimidin-2-yl)cyclobutyl)-4-oxo-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile

The title compound was prepared using procedures similar to thosedescribed for EXAMPLE 83 and 84 utilizing5-amino-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazole-3,4-dicarbonitrile(single isomer, peak 1 from SFC separation) and2-(5-fluoropyrimidin-2-yl)cyclobutane carboxylic acid to afford thetitle compound (EXAMPLE 85, single isomer) by chiral preparative SFC(Chiralpak AD-H, 21×250 mm, 10% MeOH). LCMS (ES, m/z): 424.2 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃): δ 10.70 (s, 1H), 8.68 (s, 2H), 4.09-3.94 (m, 3H),3.88 (dd, J=11.5, 3.9 Hz, 1H), 3.45 (q, J=9.9, 9.2 Hz, 1H), 3.38 (t,J=11.8 Hz, 1H), 3.28 (t, J=11.7 Hz, 1H), 2.47 (ddd, J=21.9, 11.4, 6.3Hz, 3H), 2.22 (t, J=8.4 Hz, 1H), 2.16-2.04 (m, 1H), 1.57 (d, 3H), 1.31(dq, J=20.3, 7.9, 6.3 Hz, 2H), 1.16 (qd, J=12.3, 4.6 Hz, 2H).

Example 86

6-(2-(5-fluoropyrimidin-2-yl)cyclobutyl)-4-oxo-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile

The title compound was prepared using procedures similar to thosedescribed for EXAMPLE 83 and 84 utilizing5-amino-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazole-3,4-dicarbonitrile(single isomer, peak 2 from SFC separation) and2-(5-fluoropyrimidin-2-yl)cyclobutane carboxylic acid to afford thetitle compound (EXAMPLE 86, single isomer) by chiral preparative SFC(Chiralpak AD-H, 21×250 mm, 10% MeOH). LCMS (ES, m/z): 424.2 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃): δ 10.55 (s, 1H), 8.64 (s, 2H), 4.06-3.99 (m, 2H),3.99-3.87 (m, 2H), 3.49 (q, J=9.3 Hz, 1H), 3.38 (t, J=11.6 Hz, 1H), 3.30(t, J=11.9 Hz, 1H), 2.60-2.49 (m, 1H), 2.46 (q, J=9.8, 8.9 Hz, 2H),2.21-2.04 (m, 2H), 1.37-1.27 (m, 2H), 1.18 (qd, J=12.1, 4.4 Hz, 2H).(CH₃ under solvent peak)

Examples 87-88

6-(1-methyl-2-(pyrimidin-2-yl)cyclobutyl)-4-oxo-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile

Step A: To a slurry of 2-(pyrimidin-2-yl)cyclobutanecarboxylic acid(cis-racemic, 980 mg, 5.5 mmol) in MeOH/Toluene (5 ml/22 ml) at 0° C.was added TMS diazomethane (2M in hexanes, 2.9 ml, 5.77 mmol) dropwise.The reaction mixture was warmed to ambient temperature over 3.5 hrs.Added 1 ml of trimethylsilyl diazomethane (2M in hexanes). The reactionwas continued at ambient temperature for 30 min more. The solvent wasthen concentrated. The residue was purified by column chromatography onsilica gel (Redisep gold 40 g silica cartridge), eluting with 0-100% ofEtOAc/hexanes to provide the methyl ester. LCMS (ES, m/z): 193.2 [M+H]⁺

To the methyl ester from above [methyl2-(pyrimidin-2-yl)cyclobutanecarboxylate, 192 mg, 1 mmol], in THF (4 ml)at −78° C., under N2 atmosphere, was added LHMDS (1M in THF, 1.2 ml, 1.2mmol). Maintained reaction at −78° C. for 1 hr. Then added Met (0.1 ml,1.6 mmol) dropwise. Slowly warmed reaction to 0° C., over 2 hr. Quenchedthe reaction by addition of satd NH4Cl solution (40 ml). Extracted withEtOAc (2×30 ml). The combined org layer was dried (Na2SO4), filtered andconcentrated. Crude residue was purified by column chromatography onsilica gel (Redisep gold 24 g silica cartridge), eluting with 20-100% ofEtOAc/hexanes to provide methyl1-methyl-2-(pyrimidin-2-yl)cyclobutanecarboxylate. LCMS (ES, m/z): 207.2[M+H]⁺

Step B: To methyl 1-methyl-2-(pyrimidin-2-yl)cyclobutanecarboxylate (95mg, 0.461 mmol) in THF/MeOH/water (1/1/0.5 ml) was added aq 1M LiOH(0.92 ml, 0.92 mmol). Stirred reaction at ambient temperature for 4.5hrs. At this time added more aq 1M LiOH (˜0.5 ml, −0.5 mmol), andstirred at ambient temperature overnight. Then concentrated most of thesolvent, diluted with water (15 ml). Added aq 1M HCl (till pH=1-2, by pHpaper). Extracted the with EtOAc (2×20 ml). The combined org layer wasdried (Na2SO4), filtered, concentrated to provide1-methyl-2-(pyrimidin-2-yl)cyclobutanecarboxylic acid). LCMS (ES, m/z):193.2 [M+H]⁺

Step C: To 1-methyl-2-(pyrimidin-2-yl)cyclobutanecarboxylic acid (50 mg,0.26 mmol) in dichloroethane (1.5 ml) was added(S)-5-amino-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1H-pyrazole-3,4-dicarbonitrile(80 mg, 0.26 mmol) in a vial. Added more dichloroethane (1.5 ml)followed by POCl₃ (0.1 ml, 1.07 mmol). The vial was capped and heated at75° C., overnight. Cooled to the reaction to ambient temperature, addedMeCN (˜5 ml) and water (1 ml) into r×n mix, and stirred vigorously at50° C. for 2.5 hrs (total time). Then cooled the reaction to 0° C.,diluted with EtOAc (10 ml), added satd NaHCO₃(10 ml), slowly withstirring. Further diluted with EtOAc (30 ml total), and added water (20ml). Separated org layer, extracted aq layer with EtOAc (30 ml). Thecombined org layer was washed with brine (50 ml), dried (Na2SO4),filtered and concentrated. The crude material was dissolved in MeCN (10ml), added aq 1M NaOH (4 ml), and stirred at ambient temperature for −30min. Then diluted the mixture with CH2Cl2 (30 ml), added sat'd NH4Cl (25ml)/brine (5 ml). Stirred, and separated org layer. Extracted aq layerwith CH2C12 (30 ml). The combined org layer was dried (Na2SO4), filteredand concentrated. The crude residue was purified by reverse phase HPLC.Conditions: Sunfire Prep C-18, 10 uM, 30×150 mm OBD column, flow rate 30ml/min, gradient=10-90% CH3CN (0.05% TFA) in water (0.05% TFA). Isolateda mixture of peak 3 and peak 4 (containing approx 1:2.5 ratio of peak3:peak 4). This mixture was further separated by SFC (conditions —OJ-H,21×250 mm column, 20% MeOH) to provide, Peak 2: Singleisomer-6-(1-methyl-2-(pyrimidin-2-yl)cyclobutyl)-4-oxo-1-(1-(6(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile,EXAMPLE 87. LCMS (ES, m/z): 481.3 [M+H]⁺; ¹H NMR (400 MHz, Chloroform-d)δ 12.65 (s, 1H), 8.85 (d, J=4.9 Hz, 2H), 8.82 (d, J=1.7 Hz, 1H), 8.02(dd, J=1.8, 8.2 Hz, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.31 (t, J=4.9 Hz, 1H),6.23 (q, J=7.0 Hz, 1H), 4.03 (t, J=8.7 Hz, 1H), 2.85-2.66 (m, 2H),2.43-2.28 (m, 1H), 2.10-1.98 (m, 1H), 2.05 (d, J=7.2 Hz, 3H), 1.18 (s,3H). Peak 3: Singleisomer-6-(1-methyl-2-(pyrimidin-2-yl)cyclobutyl)-4-oxo-1-(1-(6(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile,EXAMPLE 88. LCMS (ES, m/z): 481.3 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d)δ 12.66 (s, 1H), 8.91-8.79 (m, 3H), 8.04 (dd, J=2.1, 8.2 Hz, 1H), 7.72(d, J=8.1 Hz, 1H), 7.31 (t, J=4.9 Hz, 1H), 6.23 (q, J=7.4 Hz, 1H), 3.99(t, J=9.2 Hz, 1H), 2.82-2.58 (m, 2H), 2.37-2.29 (m, 1H), 2.11-1.97 (m,1H), 2.05 (d, J=7.2 Hz, 3H), 1.23 (s, 3H).

Examples 89-90

6-(2-(5-cyanopyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile

Step A: To a solution of6-(2-(5-bromopyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile(0.05 g, 0.092 mmol) in 1,4-dioxane (0.5 mL) and water (0.1 mL) wereadded t-BuBrettphos Pd G₃ (0.023 g, 0.027 mmol) and Zn(CN)₂ (0.022 g,0.18 mmol) at room temperature. The reaction mixture was degassed withN₂ for 3 times and stirred at 55° C. for 16 h under N₂. The resultingsolution was diluted with water (20 mL) and extracted with EtOAc (3×20mL). The combined organic layer was washed with brine (50 mL), driedover anhydrous Na₂SO₄ and filtered. The filtrate was concentrated undervacuum. The residue was purified by Prep-HPLC with the followingconditions: column: X Bridge C18 OBD Prep Column 100 Å, 10 μm, 19 mm×250mm; Mobile Phase A: water with 20 mmol/L NH₄HCO₃, Mobile Phase B: ACN;Flow rate: 20 mL/min; Gradient: 58% B to 76% B in 6 min; 254/210 nm. Thefractions containing desired product were combined and concentratedunder vacuum to afford 6-(2-(5-cyanopyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile.LCMS (ES, m/z): 492.2 [M+H]⁺.

Step B:6-(2-(5-Cyanopyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrilewas separated by Prep-Chiral-HPLC with the following conditions: column:CHIRALPAK IC, 2×25 cm, 5 μm; Mobile Phase A: HEX:DCM=3:1, Mobile PhaseB: EtOH; Flow rate: 16 mL/min; Gradient: 50% B to 50% B in 26 min;254/220 nm. The fractions containing desired product were combined andconcentrated under vacuum to afford6-(2-(5-cyanopyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile(peak 1, Isomer A, EXAMPLE 89). LCMS (ES, m/z): 492.2 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃) δ 11.24 (brs, 1H), 9.09 (s, 2H), 8.81 (d, J=1.6 Hz,1H), 7.99 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 6.23 (q,J=7.2 Hz, 1H), 4.05 (q, J=9.2 Hz, 1H), 3.81 (q, J=9.6 Hz, 1H), 2.77-2.69(m, 1H), 2.57-2.49 (m, 2H), 2.38-2.31 (m, 1H), 2.06 (d, J=7.2 Hz, 3H),and6-(2-(5-cyanopyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile(peak 2, Isomer B, EXAMPLE 90). LCMS (ES, m/z): 492.2 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃) δ11.28 (brs, 1H), 9.08 (s, 2H), 8.84 (d, J=1.6 Hz, 1H),8.03 (dd, J=8.0 Hz, 2.0 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 6.23 (q, J=7.2Hz, 1H), 4.02 (q, J=9.6 Hz, 1H), 3.82 (q, J=9.2 Hz, 1H), 2.71-2.63 (m,1H), 2.56-2.49 (m, 2H), 2.40-2.33 (m, 1H), 2.05 (d, J=6.8 Hz, 3H).

Example 91

6-(2-(5-cyclopropylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile

To a solution of6-(2-(5-bromopyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile(EXAMPLE 59, Isomer B) (40.00 mg, 0.073 mmol) in toluene (0.8 mL) andwater (0.2 mL) were added cyclopropylboronic acid (9.45 mg, 0.11 mmol),Cs₂CO₃ (35.8 mg, 0.11 mmol), diacetoxypalladium (1.65 mg, 7.34 μmol) andXPhos (3.50 mg, 7.34 μmol) at room temperature. The reaction mixture wasdegassed with N₂ for 3 times irradiated with microwave radiation at 140°C. for 4 h. After cooling to room temperature, the resulting mixture wasconcentrated under vacuum. The residue was diluted with water (10 mL)and extracted with EtOAc (3×10 mL). The combined organic layers wereconcentrated under vacuum. The residue was purified by Prep-HPLC withthe following conditions: column: X Select CSH Prep C18 OBD Column,19×250 mm, 5 μm; Mobile Phase A: water with 0.05% TFA, Mobile Phase B:ACN; Flow rate: 20 mL/min; Gradient: 20% B to 34% B in 15 min; 254/210nm. The collected fractions were combined and concentrated under vacuumto afford6-(2-(5-cyclopropylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile(EXAMPLE 91). LCMS (ES, m/z): 507.4. [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ12.46 (brs, 1H), 8.86 (d, J=2.0 Hz, 1H), 8.58 (s, 2H), 8.03 (dd, J=8.0Hz, 1.6 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 6.24 (q, J=7.2 Hz, 1H), 3.87(q, J=9.2 Hz, 1H), 3.73 (q, J=9.2 Hz, 1H), 2.65-2.48 (m, 1H), 2.47-2.44(m, 2H), 2.34-2.27 (m, 1H), 2.04 (d, J=7.2 Hz, 3H), 1.94-1.87 (m, 1H),1.16-1.12 (m, 2H), 0.84-0.79 (m, 2H).

Example 92

6-(2-(5-cyclopropylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile

The title compound EXAMPLE 92 was prepared as described for EXAMPLE 91using6-(2-(5-bromopyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile(EXAMPLE 58, Isomer A). LCMS (ES, m/z): 507.4 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 12.46 (brs, 1H), 8.86 (d, J=2.0 Hz, 1H), 8.58 (s, 2H), 8.03(dd, J=8.0 Hz, 1.6 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 6.24 (q, J=7.2 Hz,1H), 3.87 (q, J=9.2 Hz, 1H), 3.73 (q, J=9.2 Hz, 1H), 2.65-2.48 (m, 1H),2.47-2.44 (m, 2H), 2.34-2.27 (m, 1H), 2.04 (d, J=7.2 Hz, 3H), 1.94-1.87(m, 1H), 1.16-1.12 (m, 2H), 0.84-0.79 (m, 2H).

Examples 93, 94, 95, 96

1-(1-(2-Cyclopropylpyrimidin-5-yl)ethyl)-4-oxo-6-(2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile(Isomer A)—Example 931-(1-(2-Cyclopropylpyrimidin-5-yl)ethyl)-4-oxo-6-(2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile(Isomer C)—Example 941-(1-(2-Cyclopropylpyrimidin-5-yl)ethyl)-4-oxo-6-(2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile(Isomer BA)—Example 951-(1-(2-Cyclopropylpyrimidin-5-yl)ethyl)-4-oxo-6-(2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile(Isomer BB)—Example 96

Step A: To a solution of 1-(2-cyclopropylpyrimidin-5-yl)ethanone (1.00g, 6.17 mmol) in MeOH (10 mL) was added NaBH4 (0.467 g, 12.33 mmol) at0° C. The reaction mixture was stirred at room temperature for 2 h. Thereaction was then quenched by the addition of 2 mL of water. The residuewas diluted with water, and was extracted with ethyl acetate (3×60 mL).The combined organic layer was washed with brine (3×50 mL), dried overanhydrous Na₂SO₄ and filtered. The filtrate was concentrated underreduced pressure, the residue was purified by a silica gel columnchromatography, eluted with gradient 0%-50% ethyl acetate in petroleumether. The fractions containing desired product were combined andconcentrated to afford 1-(2-cyclopropylpyrimidin-5-yl)ethanol. LCMS (ES,m/z): 165.2 [M+H]⁺.

Step B: To a solution of 1-(2-cyclopropylpyrimidin-5-yl)ethanol (0.150g, 0.913 mmol) and4-isopropoxy-6-(2-(pyrimidin-2-yl)cyclobutyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile(0.306 g, 0.913 mmol) in toluene (1.5 mL) was added triphenylphosphine(0.599 g, 2.284 mmol) and diisopropyl azodicarboxylate (0.355 mL, 1.827mmol) at room temperature. The reaction solution was stirred at roomtemperature for 3 h. The resulting reaction was concentrated underreduced pressure and was extracted with ethyl acetate (3×50 mL). Thecombined organic layer was washed with brine (3×30 mL), dried overanhydrous Na₂SO₄ and filtered. The filtrate was concentrated underreduced pressure, the residue was purified by a silica gel columnchromatography, eluted with gradient 0%-70% ethyl acetate in petroleumether. The fractions containing desired product were combined andconcentrated to afford1-(1-(2-cyclopropylpyrimidin-5-yl)ethyl)-4-isopropoxy-6-(2-(pyrimidin-2-yl)cyclobutyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile.LCMS (ES, m/z): 482.3 [M+H]⁺.

Step C: A solution of1-(1-(2-cyclopropylpyrimidin-5-yl)ethyl)-4-isopropoxy-6-(2-(pyrimidin-2-yl)cyclobutyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile(0.350 g, 0.00 mmol) in TFA (4 mL) was stirred at room temperature for16 h. The resulting solution was filtered and the filtrate was purifiedby Prep-HPLC with the following conditions: Column: XBridge C18 OBD PrepColumn 100 Å, 10 μm, 19 mm×250 mm; Mobile Phase A: Water (20 mmol/LNH₄HCO₃), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 33% B to55% B in 8 min; 254/210 nm; to afford1-(1-(2-cyclopropylpyrimidin-5-yl)ethyl)-4-oxo-6-(2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile.LCMS (ES, m/z): 440.3 [M+H]⁺.

Step D:1-(1-(2-cyclopropylpyrimidin-5-yl)ethyl)-4-oxo-6-(2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile(0.210 g, 0.478 mmol) was separated by PREP CHIRAL HPLC with thefollowing conditions: Column: CHIRALPAK IG, 20*250 mm, 5 um; MobilePhase A: Hex—HPLC, Mobile Phase B: EtOH—HPLC; Flow rate: 20 mL/min;Gradient: 40 B to 40 B in 29 min; 220/254 nm; RT1:16.751 min; RT2:18.655min; RT:23.755 min. The fractions containing desired product werecombined and concentrated under vacuum to afford isomer A1-(1-(2-cyclopropylpyrimidin-5-yl)ethyl)-4-oxo-6-(2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile(peak 1), isomer B1-(1-(2-cyclopropylpyrimidin-5-yl)ethyl)-4-oxo-6-(2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile(peak 2) and isomer C1-(1-(2-cyclopropylpyrimidin-5-yl)ethyl)-4-oxo-6-(2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile(peak 3). Isomer A (Peak 1, EXAMPLE 93): LCMS (ES, m/z): 440.3 [M+H]⁺.¹H NMR (400 MHz, CDCl₃) δ 12.34 (s, 1H), 8.85 (d, J=4.9 Hz, 2H), 8.74(s, 2H), 7.37-7.30 (m, 1H), 6.11 (q, J=7.1 Hz, 1H), 3.93 (q, J=9.4 Hz,1H), 3.80 (q, J=9.5 Hz, 1H), 2.77-2.62 (m, 1H), 2.59-2.48 (m, 2H),2.38-2.25 (m, 2H), 2.05 (d, J=7.3 Hz, 3H), 1.22-1.08 (m, 4H). Isomer C(Peak 3, EXAMPLE 94): LCMS (ES, m/z): 440.3 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 12.29 (s, 1H), 8.85 (d, J=5.0 Hz, 2H), 8.69 (s, 2H), 7.37-7.30(m, 1H), 6.12 (q, J=7.2 Hz, 1H), 3.95 (q, J=9.5 Hz, 1H), 3.78 (q, J=9.4Hz, 1H), 2.81-2.66 (m, 1H), 2.59-2.48 (m, 2H), 2.40-2.20 (m, 2H), 2.05(d, J=7.2 Hz, 3H), 1.20-1.06 (m, 4H).

Step E: Isomer B (peak 2 of step D)1-(1-(2-cyclopropylpyrimidin-5-yl)ethyl)-4-oxo-6-(2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile(90 mg, 0.205 mmol) was separated by PREP CHIRAL HPLC with the followingconditions: Column: (R,R)-WHELK-O1-Kromasil, 5 cm*25 cm (5 um); MobilePhase A: Hex—HPLC, Mobile Phase B: EtOH—HPLC; Flow rate: 20 mL/min;Gradient: 30 B to 30 B in 22 min; 254/220 nm. The collected fractionswere combined and concentrated under vacuum to afford the faster elutingisomer BA1-(1-(2-cyclopropylpyrimidin-5-yl)ethyl)-4-oxo-6-(2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile.The collected fractions were combined and concentrated under vacuum toafford the slower eluting isomer BB1-(1-(2-cyclopropylpyrimidin-5-yl)ethyl)-4-oxo-6-(2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile.Isomer BA (Faster eluting, Peak 1, EXAMPLE 95): LCMS (ES, m/z): 440.3[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 12.34 (s, 1H), 8.85 (d, J=4.9 Hz, 2H),8.73 (s, 2H), 7.37-7.30 (m, 1H), 6.11 (q, J=7.2 Hz, 1H), 3.93 (q, J=9.4Hz, 1H), 3.80 (q, J=9.5 Hz, 1H), 2.76-2.62 (m, 1H), 2.59-2.48 (m, 2H),2.40-2.23 (m, 2H), 2.04 (d, J=7.2 Hz, 3H), 1.21-1.07 (m, 4H). Isomer BB(Slower eluting, Peak 2, EXAMPLE 96): LCMS (ES, m/z): 440.3 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 12.28 (s, 1H), 8.85 (d, J=5.0 Hz, 2H), 8.69 (s,2H), 7.37-7.30 (m, 1H), 6.12 (q, J=7.2 Hz, 1H), 3.95 (q, J=9.5 Hz, 1H),3.78 (q, J=9.4 Hz, 1H), 2.73 (p, J=10.3 Hz, 1H), 2.59-2.48 (m, 2H),2.39-2.22 (m, 2H), 2.05 (d, J=7.2 Hz, 3H), 1.20-1.06 (m, 4H).

Example 97

6-(2-(5-Methoxypyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile

Step A: To a solution of3-((benzyloxy)methyl)-6-(2-(5-methoxypyrimidin-2-yl)cyclobutyl)-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one(0.05 g, 0.085 mmol) in DCM (2 mL) was added boron trichloride (0.34 mL,0.34 mmol) at −78° C. The reaction solution was stirred −40° C. for 2 h.The resulted solution was quenched with MeOH at −78° C. and concentratedunder vacuum. The residue was purified by Column: XBridge C18 OBD PrepColumn, 100 Å, 5 μm, 19 mm×250 mm; Mobile Phase A: water with 20 mmol/LNH₄HCO₃, Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 20% B to80% B in 9 min; 254/210 nm. The fractions containing desired productwere combined and concentrated to afford3-(hydroxymethyl)-6-(2-(5-methoxypyrimidin-2-yl)cyclobutyl)-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one.LCMS (ES, m/z): 502.2 [M+H]⁺.

Step B: To a solution of3-(hydroxymethyl)-6-(2-(5-methoxypyrimidin-2-yl)cyclobutyl)-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one(0.10 g, 0.20 mmol) in DCM (4 mL) was added Dess-Martin Periodinane(0.09 g, 0.20 mmol). The reaction mixture was stirred at roomtemperature for 1 h. The reaction mixture was quenched with aq. NaHCO₃(sat., 3 mL) and aq. Na2S2O3 (sat., 3 mL). The resulting mixture wasstirred for 30 min. The reaction mixture was extracted with DCM (3×10mL). The combined organic layers was dried over anhydrous Na2SO4 andfiltered. The filtrate was concentrated under vacuum. The residue waspurified by silica gel column chromatography, eluted with gradient50%-100% EtOAc in Petroleum ether. The fractions containing desiredproduct were combined and concentrated under vacuum to afford6-(2-(5-methoxypyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbaldehyde.LCMS (ES, m/z): 500.1 [M+H]⁺.

Step C: To a solution of6-(2-(5-methoxypyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbaldehyde(45.00 mg, 0.090 mmol) in ACN (0.5 mL) at room temperature under N₂ wereadded hydroxylamine hydrochloride (9.39 mg, 0.14 mmol) and DIPEA (0.063mL, 0.36 mmol). The reaction mixture was stirred at room temperature for5 min. A 50% solution of2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (115 mg,0.36 mmol) was added dropwise to the reaction mixture. The reactionmixture was stirred at 80° C. for 8 h. The solvent was removed undervacuum. The residue was purified by Prep-HPLC with the followingconditions: column: X Bridge BEH C18 OBD Prep Column, 5 μm, 19 mm×250mm; Mobile Phase A: water with 10 mmol/L NH₄HCO₃ and 0.1% NH₃.H₂O,Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 20% B to 70% B in 9min; 254/210 nm. The fractions containing desired product were combinedand concentrated under vacuum to afford6-(2-(5-methoxypyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile.LCMS (ES, m/z): 497.2 [M+H]⁺.

TABLE 4 Exact Mass Chiral HPLC Ex. Structure Name [M + H]⁺ Condition;Peak #  98

1-((S)-1-(5- fluoropyridin-2-yl)ethyl)- 4-oxo-6-(2-(pyrimidin-2-yl)cyclobutyl)-4,5- dihydro-1H- pyrazolo[3,4- d]pyrimidine-3-carbonitrile 417.2 From final reaction mixture the first eluted peakusing Condition J was further separated by Condition H; 1  99

1-((S)-1-(5- fluoropyridin-2-yl)ethyl)- 4-oxo-6-(2-(pyrimidin-2-yl)cyclobutyl)-4,5- dihydro-1H- pyrazolo[3,4- d]pyrimidine-3-carbonitrile 417.2 From final reaction mixture the first eluted peakusing Condition J was further separated by Condition H; 2 100

1-((S)-1-(5- fluoropyridin-2-yl)ethyl)- 4-oxo-6-(2-(pyrimidin-2-yl)cyclobutyl)-4,5- dihydro-1H- pyrazolo[3,4- d]pyrimidine-3-carbonitrile 417.2 Condition J; 2 101

1-((S)-1-(5- fluoropyridin-2-yl)ethyl)- 4-oxo-6-(2-(pyrimidin-2-yl)cyclobutyl)-4,5- dihydro-1H- pyrazolo[3,4- d]pyrimidine-3-carbonitrile 417.2 Condition J; 3 102

6-(2-(5-(difluoromethyl)- pyrimidin-2-yl)cyclo-butyl)-4-oxo-1-((S)-1-(6- (trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro- 1H-pyrazolo[3,4- d]pyrimidine-3- carbonitrile517.1 Condition B; 1 103

6-(2-(5-(difluoromethyl)- pyrimidin-2-yl)cyclo-butyl)-4-oxo-1-((S)-1-(6- (trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro- 1H-pyrazolo[3,4- d]pyrimidine-3- carbonitrile517.1 From final reaction mixture the second eluted peak on Condition Bwas further separated by Condition C; 1 104

6-(2-(5-(difluoromethyl)- pyrimidin-2-yl)cyclo-butyl)-4-oxo-1-((S)-1-(6- (trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro- 1H-pyrazolo[3,4- d]pyrimidine-3- carbonitrile517.1 From final reaction mixture the second eluted peak on Condition Bwas further separated by Condition C; 2 105

6-(2-(5-(difluoromethyl)- pyrimidin-2-yl)cyclo-butyl)-4-oxo-1-((S)-1-(6- (trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro- 1H-pyrazolo[3,4- d]pyrimidine-3- carbonitrile517.1 Condition B; 3 106

  Isomer A 6-(2-(5-chloropyrimidin- 2-yl)cyclobutyl)-4-oxo-1-(1-(6-(trifluoromethyl)- pyridin-3-yl)ethyl)-4,5- dihydro-1H-pyrazolo[3,4- d]pyrimidine-3- carbonitrile 501.1 Condition B; 1 107

  Isomer BA 6-(2-(5-chloropyrimidin- 2-yl)cyclobutyl)-4-oxo-1-(1-(6-(trifluoromethyl)- pyridin-3-yl)ethyl)-4,5- dihydro-1H-pyrazolo[3,4- d]pyrimidine-3- carbonitrile 501.1 From final reactionmixture the second eluted peak on Condition B was further separated byCondition C; 1 108

  Isomer BB 6-(2-(5-chloropyrimidin- 2-yl)cyclobutyl)-4-oxo-1-(1-(6-(trifluoromethyl)- pyridin-3-yl)ethyl)-4,5- dihydro-1H-pyrazolo[3,4- d]pyrimidine-3- carbonitrile 501.1 From final reactionmixture the second eluted peak on Condition B was further separated byCondition C; 2 109

  Isomer C 6-(2-(5-chloropyrimidin- 2-yl)cyclobutyl)-4-oxo-1-(1-(6-(trifluoromethyl)- pyridin-3-yl)ethyl)-4,5- dihydro-1H-pyrazolo[3,4- d]pyrimidine-3- carbonitrile 501.1 Condition B; 3

The following compounds were prepared according to the general procedureprovided in the examples and procedures herein using known or preparedstarting materials, as described in the reaction schemes and examplesherein, such as described for Example 97, using appropriate startingmaterials and purification conditions. The requisite starting materialsare either prepared as described in the intermediates section,commercially available, or may be prepared from commercially availablereagents using conventional reactions well known in the art withoutundue experimentation.

Examples 110-111

6-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile(EXAMPLE 110) and6-((1S,2S)-2-(4,6-dimethylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile(Example 111)

To a solution of6-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile(9 mg, 0.02 mmol), Ir(dF (CF₃) ppy)₂(dtbbpy)]PF₆ photocatalyst (1.09 mg,0.96 μmol, 5 mol %) in CAN (106 μL)/TFA (106 μL), tert-butylperacetate(10.8 μL, 0.058 mmol) was added and the mixture was stirred at roomtemperature for 12 hours under blue LED lights (Merck G2 photoreactor,82% LED intensity). After 12 hours, LCMS showed some amount of productformation. Another round of tert-butylperacetate (10.8 μL, 0.058 mmol)was added and the solution was stirred at room temperature for further12 hours under blue LED lights. LCMS indicated formation of thebis-methylated product along with significant amount of themono-methylated product. The reaction mixture was concentrated underreduced pressure, dissolved in 1.5 mL DMSO, filtered through a 0.45micron HPLC frit and purified by reverse phase chromatography (Column:Waters Xbridge C18 Column, 130 Å, 19×150 mm, 5 um, Flow=25 ml/min,linear gradient: starting with 30% CAN/water to 70% CAN/water bufferedwith 0.16% ammonium hydroxide (pH 10)) to give the product EXAMPLE 110and EXAMPLE 111. EXAMPLE 110: ¹H NMR (500 MHz, CDCl₃) δ 13.03 (s, 1H),8.89 (s, 1H), 8.67 (d, J=5.1 Hz, 1H), 8.06 (d, J=8.1 Hz, 1H), 7.74 (d,J=8.2 Hz, 1H), 7.17 (d, J=5.0 Hz, 1H), 6.27 (q, J=7.1 Hz, 1H), 3.88 (q,J=9.6 Hz, 1H), 3.77 (q, J=9.4 Hz, 1H), 2.68 (s, 3H), 2.61 (q, J=9.8 Hz,1H), 2.51 (dt, J=9.6, 16.7 Hz, 2H), 2.34 (d, J=8.3 Hz, 1H), 2.07 (d,J=7.1 Hz, 3H). LCMS (ES, m/z): [M+H]⁺: 481.4. EXAMPLE 111: ¹H NMR (500MHz, CDCl₃) δ 13.03 (br s, 1H), 8.90 (s, 1H), 8.05 (d, J=6.5 Hz, 1H),7.73 (d, J=8.2 Hz, 1H), 7.04 (s, 1H), 6.35 (m, 1H), 4.09-3.48 (m, 2H),2.62 (s, 6H), 2.53-2.44 (m, 2H), 2.34 (d, J=8.0 Hz, 1H), 2.06 (d, J=7.1Hz, 3H). LCMS (ES, m/z): [M+H]⁺: 495.4

Example 112

6-((1S,2S)-2-(4-(difluoromethyl)pyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)-pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitriletrifluoroacetic acid salt

To a solution of6-((1S,2S)-2-(4-methylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile(9 mg, 0.02 mmol), 10-methyl-9-(2,4,6-trimethylphenyl) acridiniumtetrafluoroborate photocatalyst (0.38 mg, 0.96 μmol, 5 mol %), zincdifluoromethanesulfinate (17.11 mg, 0.058 mmol) in CAN (150 μL)/water(150 μL), potassium persulfate (15.65 mg, 0.058 mmol) and TFA (1.48 μL,0.02 mmol) were added and the mixture was stirred at room temperaturefor 12 hours under blue LED lights (Merck G2 photoreactor, 91% LEDintensity). After 12 hours, LCMS showed some amount of productformation. Another round of zinc difluoromethane-sulfinate (17.11 mg,0.058 mmol) and potassium persulfate (15.65 mg, 0.058 mmol) were addedand the solution was stirred at room temperature for further 12 hoursunder blue LED lights (Merck G2 photoreactor, 100% LED intensity). Thereaction mixture was concentrated under reduced pressure, dissolved in1.5 mL DMSO, filtered through a 0.45 micron HPLC frit and purified byreverse phase chromatography (Column: Waters CSH C18 Column, 130 Å,19×150 mm, 5 um, Flow=25 ml/min, linear gradient: starting with 40%CAN/water to 85% CAN/water buffered with 0.1% TFA) to give the productEXAMPLE 112 TFA salt. ¹H NMR (500 MHz, CDCl₃) δ 11.96 (s, 1H), 8.06 (dd,J=8.2, 1.9 Hz, 1H), 7.74 (d, J=8.2 Hz, 1H), 7.62 (d, J=5.1 Hz, 1H), 6.66(t, J=54.5 Hz, 1H), 6.26 (q, J=7.1 Hz, 1H), 3.98 (q, J=9.4 Hz, 1H), 3.83(q, J=9.5 Hz, 1H), 2.68 (p, J=10.0 Hz, 1H), 2.60-2.48 (m, 2H), 2.37 (q,J=8.4 Hz, 1H), 2.07 (d, J=7.2 Hz, 3H). LCMS (ES, m/z): [M+H]⁺: 517.4

TABLE 5 LCMS Example Structure Name (M + H)⁺ 113

6-((1S,2S)-2-(4,6-di-tert- butylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)- 1-(6-(trifluoromethyl)-pyridin-3-yl)ethyl)-4,5- dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile 579.4 114

6-((1S,2S)-2-(4- cyclopropyl-pyrimidin-2- yl)cyclobutyl)-4-oxo-1-((S)-1-(6- (trifluoromethyl)pyridin-3- yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine- 3-carbonitrile 507.3 115

6-((1R,2R)-2-(4-(difluoro- methyl)pyrimidin-2- yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)- pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4- d]pyrimidine-3-carbonitrile 517.5 116

6-((1R,2R)-2-(4,6- bis(difluoromethyl)pyrimidin-2-yl)cyclobutyl)-4-oxo-1- ((R)-1-(6-(trifluoromethyl)-pyridin-3-yl)ethyl)-4,5- dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile 567.4 117

6-((1R,2R)-2-(4- methylpyrimidin-2- yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)- pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4- d]pyrimidine-3-carbonitrile 481.2 118

6-((1R,2R)-2-(4,6-di-tert- butylpyrimidin-2- yl)cyclobutyl)-4-oxo-1-((R)-1-(6-(trifluoromethyl)- pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4- d]pyrimidine-3-carbonitrile 579.5 119

6-((1R,2R)-2-(4- methylpyrimidin-2- yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)- pyridin-3-yl)ethyl)-4,5-dihvdro-1H-pyrazolo[3,4- d]pyrimidine-3-carbonitrile 481.3 120

6-((1R,2R)-2-(4,6- dimethylpyrimidin-2- yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)- pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4- d]pyrimidine-3-carbonitrile 495.3 121

6-(2-(4-(tert- butyl)pyrimidin-2- yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)- pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4- d]pyrimidine-3-carbonitrile 523.4 122

6-((1R,2R)-2-(4,6-di-tert- butylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)- 1-(6-(trifluoromethyl)-pyridin-3-yl)ethyl)-4,5- dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile 579.5 123

6-((1R,2R)-2-(4- (difluoromethyl)pyrimidin- 2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)- pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4- d]pyrimidine-3-carbonitrile 517.3 124

6-((1R,2R)-2-(4- cyclopropylpyrimidin-2- yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)- pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4- d]pyrimidine-3-carbonitrile 507.1

The following compounds were prepared according to the general procedureprovided in the examples and procedures herein using known or preparedstarting materials, as described in the reaction schemes and examplesherein, such as described for Examples 110-112, using appropriatestarting materials and purification conditions. The compounds wereisolated as the 2,2,2-trifluoroacetate salt. The requisite startingmaterials are either prepared as described in the intermediates section,commercially available, or may be prepared from commercially availablereagents using conventional reactions well known in the art withoutundue experimentation.

TABLE 6 PDE9 IMAP Ki Example (nM) 1 27.3 2 0.2 3 32.1 4 4.8 5 15.9 6 0.17 2.8 8 4.7 9 123.7 10 4.8 11 44.3 12 9.3 13 0.1 14 1.5 15 109.5 16 3 170.4 18 11.3 19 12.1 20 0.01 21 4.5 22 1.8 23 25 24 1.8 25 31.9 26 0.1 2719.6 28 0.5 29 271.8 30 2.3 31 2.2 32 154.5 33 0.04 34 318.6 35 1.2 36329.2 37 50.4 38 >607.5 39 >607.5 40 0.13 41 8 42 >607.5 43 2 44 82.3 458.9 46 164.2 47 0.22 48 0.9 49 103.9 50 >607.5 51 >607.5 52 147.8 53 0.854 >607.5 55 493.4 56 12.6 57 0.01 58 26.9 59 0.12 60 86.7 61 0.08 620.01 63 5.6 64 >67.5 65 >67.5 66 >67.5 67 >67.5 68 >67.5 69 >67.570 >67.5 71 >67.5 72 54.6 73 2 74 6.2 75 0.02 76 353.5 77 153.3 78 1.179 17.3 80 0.09 81 1.6 82 0.23 83 10.8 84 0.25 85 >607 86 >607 87 249.588 0.7 89 139.8 90 0.3 91 0.01 92 55.7 93 0.03 94 1.3 95 1.5 96 37.8 970.15 98 321.4 99 392.2 100 1.7 101 16 102 164.8 103 33.9 104 0.18 10521.8 106 26.7 107 175.1 108 0.2 109 24 110 0.05 111 0.04 112 0.13 1130.27 114 0.04 115 25.3 116 8.3 117 3.9 118 74.7 119 36.7 120 23.3 12123.7 122 321.4 123 19.2 124 28.9

The following table shows representative data for the compounds of theExamples as PDE9 inhibitors as determined by the assays describedherein. In this table, the PDE9 K_(i) is a measure of the ability of thetest compound to inhibit the action of the PDE9 enzyme. Such results areindicative of the intrinsic activity of the compounds for use asinhibitors of the PDE9 enzyme.

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.

1-12. (canceled)
 13. A compound which is selected from:1-((S)-1-(4-fluorophenyl)ethyl)-4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;6-((1S,2S)-2-(5-(difluoromethoxy)pyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;6-((1S,2S)-2-(5-fluoropyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;1-((S)-1-(2-cyclopropylpyrimidin-5-yl)ethyl)-4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;6-((1S,2S)-2-(4-cyclopropylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)-pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;or a pharmaceutically acceptable salt thereof.
 14. The compound of claim13 which is:1-((S)-1-(4-fluorophenyl)ethyl)-4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;or a pharmaceutically acceptable salt thereof.
 15. The compound of claim14 which is:1-((S)-1-(4-fluorophenyl)ethyl)-4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile.16. The compound of claim 14 which is:1-((S)-1-(4-fluorophenyl)ethyl)-4-oxo-6-(1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile,in the form of a pharmaceutically acceptable salt thereof.
 17. Thecompound of claim 13 which is:4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;or a pharmaceutically acceptable salt thereof.
 18. The compound of claim17 which is:4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile.19. The compound of claim 17 which is:4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;in the form of a pharmaceutically acceptable salt thereof.
 20. Thecompound of claim 13 which is:6-((1S,2S)-2-(5-(difluoromethoxy)pyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;or a pharmaceutically acceptable salt thereof.
 21. The compound of claim20 which is:6-((1S,2S)-2-(5-(difluoromethoxy)pyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile.22. The compound of claim 20 which is:6-((1S,2S)-2-(5-(difluoromethoxy)pyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;in the form of a pharmaceutically acceptable salt thereof.
 23. Thecompound of claim 13 which is:6-((1S,2S)-2-(5-fluoropyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;or a pharmaceutically acceptable salt thereof.
 24. The compound of claim23 which is:6-((1S,2S)-2-(5-fluoropyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile.25. The compound of claim 23 which is:6-((1S,2S)-2-(5-fluoropyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;in the form of a pharmaceutically acceptable salt thereof.
 26. Thecompound of claim 13 which is:1-((S)-1-(2-cyclopropylpyrimidin-5-yl)ethyl)-4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;or a pharmaceutically acceptable salt thereof.
 27. The compound of claim26 which is:1-((S)-1-(2-cyclopropylpyrimidin-5-yl)ethyl)-4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile.28. The compound of claim 26 which is:1-((S)-1-(2-cyclopropylpyrimidin-5-yl)ethyl)-4-oxo-6-((1S,2S)-2-(pyrimidin-2-yl)cyclobutyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;in the form of a pharmaceutically acceptable salt thereof.
 29. Thecompound of claim 13 which is:6-((1S,2S)-2-(4-cyclopropylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)-pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;or a pharmaceutically acceptable salt thereof.
 30. The compound of claim29 which is:6-((1S,2S)-2-(4-cyclopropylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)-pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile.31. The compound of claim 29 which is:6-((1S,2S)-2-(4-cyclopropylpyrimidin-2-yl)cyclobutyl)-4-oxo-1-((S)-1-(6-(trifluoromethyl)-pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;in the form of a pharmaceutically acceptable salt thereof.
 32. Apharmaceutical composition comprising an inert carrier and a compound ofclaim 13, or a pharmaceutically acceptable salt thereof.
 33. A methodfor inhibiting phosphodiesterase 9 activity in a mammalian patient,comprising administering to the mammalian patient a therapeuticallyeffective amount of a compound of claim 13, or a pharmaceuticallyacceptable salt thereof.
 34. The method of claim 33, wherein themammalian patient has a disorder or disease associated withphosphodiesterase 9 dysfunction.
 35. The method of claim 34, wherein thedisorder or disease associated with phosphodiesterase 9 dysfunction isselected from the group consisting of hypertension, heart failure, acardiovascular disease, a cerebrovascular disease, and a chronic kidneydisease.
 36. The method of claim 34, wherein the disorder or diseaseassociated with phosphodiesterase 9 dysfunction is selected from thegroup consisting of drug induced psychosis, a psychotic disorder, adelusional disorder, a movement disorder, a neurodegenerative disorderand an anxiety disorder.